Exhibit 10.58



 








EXHIBIT
10.58



***Text Omitted and Filed Separately
Confidential Treatment
Requested
Under 17 C.F.R. §§ 200.80(b)(4)
and
240.24b-2(b)(1)




IL-13 Development and Manufacturing Agreement




 



 



 



 



Biotecnol SA




And




IDM




 









 





			
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CONTENTS




	 	 	 	 	 	 	 	 	 
	 	 	CLAUSE	 	PAGE	 
	 
	 	1.	 	DEFINITIONS & PURPOSE	 	 	1	 
	 
	 	2.	 	 OBLIGATIONS OF BIOTECNOL	 	 	6	 
	 
	 	3.	 	OBLIGATIONS OF IDM	 	 	7	 
	 
	 	4.	 	 PAYMENT	 	 	8	 
	 
	 	5.	 	PROGRAMME MANAGEMENT	 	 	11	 
	 
	 	6.	 	SUB-CONTRACTING AND OUTSOURCING	 	 	12	 
	 
	 	7.	 	INTELLECTUAL PROPERTY RIGHTS	 	 	14	 
	 
	 	8.	 	CONFIDENTIALITY	 	 	16	 
	 
	 	9.	 	WARRANTIES AND DISCLAIMER	 	 	17	 
	 
	 	10.	 	DURATION AND TERMINATION	 	 	18	 
	 
	 	11.	 	EFFECT OF TERMINATION	 	 	19	 
	 
	 	12.	 	FORCE MAJEURE	 	 	20	 
	 
	 	13.	 	COSTS	 	 	20	 
	 
	 	14.	 	VARIATIONS	 	 	20	 
	 
	 	15.	 	WAIVER	 	 	21	 
	 
	 	16.	 	INVALIDITY	 	 	21	 
	 
	 	17.	 	NOTICES	 	 	21	 
	 
	 	18.	 	NO PARTNERSHIP	 	 	22	 
	 
	 	19.	 	ASSIGNMENT	 	 	22	 
	 
	 	20.	 	GOVERNING LAW AND JURISDICTION	 	 	23	 
	 
	 	21.	 	ENTIRE AGREEMENT	 	 	23	 
	 
	 	 	 	 	 	 	 	 
	SCHEDULE 1 Programme	 	 	25	 
	SCHEDULE 2	 	 	25	 






 









 





THIS AGREEMENT is dated November 4, 2003




BETWEEN:





	(1)	 	BIOTECNOL SA having its principal place of business at Taguspark, Edificio Inovacao IV, 809
Porto Salvo, 2780-920 Oeiras, Portugal (“Biotecnol”); and
	 
	(2)	 	IDM IMMUNO-DESIGNED MOLECULES S.A. registered at Paris RCS under 632 382 263 and having its
main offices at 172 rue de Charonne 75011 Paris FRANCE (“IDM”).





RECITALS





	(A)	 	Biotecnol is a biotechnology company which owns or is licensee of systems for recombinant
protein expression in the bacterium Escherichia coli (“E. coli”) and has expertise and
know-how in the design and optimisation of recombinant protein production processes,
expression of recombinant proteins, fermentation media optimisation, fermentation design,
protein purification, protein characterisation, design and the scale-up of integrated
processes for the production of recombinant proteins, and in the general use of E. coli
as a host for the expression of proteins.
	 
	(B)	 	IDM is a biopharmaceutical company developing a new family of immunotherapy products called
Cell Drugs made of dendritic cells loaded with antigens to fight cancer , infectious diseases
and auto-immune diseases.
	 
	(C)	 	IDM and Biotecnol signed a Prototype Production Contract (“Initial Contract”) on March 8,
2001. The objective of the collaboration was to enable IDM to obtain a preliminary process for
the purposes of production of the molecule Interleukine 13 (“IL-13”) using E. coil
as a host. Based on the final report sent by Biotecnol, a success fee of [...***...] as
been paid on August 2002. Intellectual Property Rights resulting from the performance of the
Initial Contract shall be considered as Biotecnol’s Background Technology. The Initial
Contract shall be replaced by the Agreement.
	 
	(D)	 	Biotecnol and IDM have been pursuing the IL-13 development since April 1st,
2003, based on a letter of intent executed by the Parties (“Letter of Intent” or “LOI”).
	 
	 	 	THE PARTIES AGREE AS FOLLOWS:
	 
	1.	 	DEFINITIONS & PURPOSE
	 
	 	 	In this Agreement, unless the context otherwise requires, the following words and
expressions have the following meaning:
	 
	 	 	“Affiliate” means any company, partnership or other entity which directly or indirectly
controls, is controlled by or is under the common control of either party, as applicable;
“control” means possession, directly or indirectly, of more than 50% of the voting stock or
other ownership interest of another person or the power to direct or cause the direction of
the management and policies of such person.

“Agreement” means this agreement, the Programme and other schedules.

“Background Rights” means the Biotecnol Background Patents, the Biotecnol





	 	 	 	 	 
	 

	 	*
	 	Confidential Treatment Requested

under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 





			
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	 	 	Background Technology, the IDM Background Patents, the IDM Background Technology and
the IDM Materials.
	 
	 	 	“Biotecnol Background Patents” means:
	 
	(a)	 	all patent applications and patents, and any and all patents issuing therefrom,
including utility models, design patents and inventor’s certificates, owned,
controlled or licensed by Biotecnol as of the Effective Date or developed, acquired,
licensed or otherwise obtained by Biotecnol, other than from IDM, during the term of
this agreement, together with any and all substitutions, extensions (including
supplemental protection certificates), provisionals, divisionals, continuations,
continuations-in-part, re-examinations, re-issues, renewals, revalidations, additions,
substitutions, confirmations and registrations, as well as all foreign counterparts or
equivalents thereof anywhere in the world, including without limitation all such
patents and patent applications.
	 
	(b)	 	all patent applications owned, controlled or licensed by Biotecnol that may be filed
anywhere in the world, which either are based on or claim priority from any of the
foregoing patent applications or patents, and any and all patents which may issue from
any such patent applications;




excluding all patents and patent applications exclusively relating to inventions within the
Foreground Rights.



“Biotecnol Background Technology” means Biotecnol’s proprietary information, know-how,
knowledge, experience, inventions, improvements, processes, technology, ideas,
instructions, data and other technical or commercial information and materials, including
without limitation the Expression Vectors, the Host Strains and the Expression Systems, and
Biotecnol’s proprietary molecular chaperones, fusion partners, fermentation media and
know-how and protein purification techniques, whether owned, controlled or licensed by
Biotecnol, but excluding any Foreground Rights; the parties agree that inventions and
results from the performance of the Initial Contract shall be considered as Biotecnol
Background Technology.



“Business Day” means any day on which banks generally are open in the City of Lisbon and
Paris for the transaction of normal banking business.



“Confidential Information” means all oral or written information, data, Intellectual Property
Rights, processes, procedures, methods, know-how, knowledge, experience and other valuable
information relating to either party’s business, whether of a financial, technical, scientific,
R&D-related, marketing, sales or legal nature, or pertaining to its representatives, officers,
employees, agents, consultants or advisers, disclosed or provided by such party to the other party
pursuant to or in connection with the Agreement. The Biotecnol Background Technology and all
confidential information, know-how, processes, procedures and methods employed by Biotecnol in the
Programme shall constitute Confidential Information of Biotecnol; the IDM Background Technology,
the IDM Materials and all confidential information, know-how, processes, procedures and methods
employed by IDM in the Programme shall constitute Confidential Information of IDM; the Foreground
Rights


 









 






and all confidential information, know-how, processes, procedures and methods employed by both
Parties in the Programme shall constitute Confidential Information of the Parties; the Parties
agree to consider any information coming from the Sanofi-Synthelabo SA. or Sanofi-Synthelabo S.A.’s
Affiliates as Confidential Information.




“Date” means the targeted date for release of Finished Product, i.e. referred to as T10P3 in
SCHEDULE 1.



“Delivery” means the written acknowledgement in Joint Management Committee minutes, in connection
to the Programme, stating that any agreed milestone as described on the Programme has been
achieved.



“Drug Master File or DMF” means a drug master file or equivalent required for any regulatory
approval from Regulatory Authority.



“Effective Date” means April 1st, 2003.



“End of the Programme” means the end of the 36 (thirty six) months’ stability studies on Finished
Product.



“Expression System” means a Host Strain containing an Expression Vector directing the production of
a protein, selected by Biotecnol pursuant to and for the purposes of this Agreement, and utilised
by Biotecnol in the Programme.



“Expression Vectors” means any vectors or gene expression regulatory elements, whether in
combination or not, owned, controlled or licensed by Biotecnol, in each case for use in one or more
Host Strains.



“Field” means the use of IL-13 to differentiate monocytes into dendritic cells to develop
therapeutic vaccines.



“Finished Product” means the Product formulated in vials usable for phase III clinical trial.



“Foreground Rights” means all patents, patent applications, know-how, inventions and improvements,
whether patentable or protectable through trade secret, resulting or emerging from or generated in
the course of the Programme, if any.



“Host Strain” means any strain of E. coli owned by or the use of which is licensed to Biotecnol.



"IDM” shall mean Immuno-Designed Molecules S.A. and its affiliated companies.



“IDM Background Patents” means :

(a) all patent applications and patents, and any and all patents issuing therefrom, including
utility models, design patents and inventor’s certificates, owned, controlled or licensed by IDM as
of the Effective Date or developed, acquired, licensed or otherwise obtained by IDM, other than
from Biotecnol, during the term of this Agreement, together with any and all substitutions,
extensions (including supplemental protection certificates), provisionals, divisionals,
continuations, continuations-in-part, re-examinations, re-issues, renewals, revalidations,
additions, substitutions, confirmations and registrations, as well as all foreign



 









 





			
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counterparts or equivalents thereof anywhere in the world, including without limitation all such
patents and patent applications.



(b) all patent applications owned, controlled or licensed by IDM that may be filed anywhere in the
world, which either are based on or claim priority from any of the foregoing patent applications or
patents, and any and all patents which may issue from any such patent applications.



"IDM Background Technology” means IDM’s proprietary information, know-how, knowledge, experience,
inventions, improvements, processes, technology, ideas, instructions, data and other technical or
commercial information, in the possession of IDM or developed, acquired, licensed or otherwise
obtained by IDM other than from Biotecnol, excluding any Foreground Rights.



“IDM Materials” means 5 vials of [...***...] and any and all other materials IDM transferred to
Biotecnol for the purpose of the Agreement.



“Intellectual Property Rights” means any and all trade marks, rights in designs, get-up, trade,
business or domain names, copyrights, future copyrights, patents, rights in databases (whether
registered or not and any applications to register or rights to apply for registration of any of
the foregoing), rights in inventions, know how, trade secrets and other confidential information
and all other intellectual property rights of a similar or corresponding nature which may now or in
the future subsist in any part of the world.



“Manufacturing Period” means the [...***...] period starting upon release of the first successful
Finished Product batch.



“Process” shall mean the cGMP manufacturing, control, testing and release processes of the Finished
Product.



“Product[s]” means recombinant cGMP Interleukine-13 (“IL-13”).



“Programme” means the work to be performed by the Biotecnol pursuant to this Agreement, as more
specifically set out in SCHEDULE 1. It is made of the Part 1 and Part 2, the later one being
subject to future financial charges which are not included in actual consideration.



“Programme Materials” means all cells, molecular construction, working cell bank, master cell bank,
assays, batches or production lots of Product, generated in the course of the Programme, containing
or specifically dedicated to IL-13 development and manufacturing together with all documentation
and descriptions of and data pertaining thereto, other than Biotecnol Background Technology and IDM
Materials and IDM Background Technology.



“Regulatory Authority” shall mean, with respect to any country, any regulatory agency, ministry,
department or other governmental body having authority in such country substantially equivalent to
the authority of the EMEA or the FDA in the European Union and the United States of America
respectively, to regulate the development, manufacture, marketing, promotion or sale of
pharmaceutical products.



	 	 	 	 	 
	 

	 	*
	 	Confidential Treatment Requested

under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 





“Value Added Tax” means Value Added Tax or any other tax of a similar nature that may be
substituted for or levied in addition to it, in each case at the rate current from time to time.




	1.2	 	In this agreement unless otherwise specified, reference to:






	 	(a)	 	a party means a party to this Agreement and includes its permitted assignees
and/or the respective successors in title to substantially the whole of its
undertaking;
	 
	 	(b)	 	a person includes any person, individual, company, firm, corporation,
government, state or agency of a state or any undertaking (whether or not having
separate legal personality and irrespective of the jurisdiction in or under the law of
which it was incorporated or exists);
	 
	 	(c)	 	a statute or statutory instrument or any of their provisions is to be
construed as a reference to that statute or statutory instrument or such provision as
the same may have been or may from time to time hereafter be amended or re-enacted;
	 
	 	(d)	 	words denoting the singular shall include the plural and vice versa and words
denoting any gender shall include all genders.






	1.3	 	The index to and headings in this agreement are for information only and are to be ignored in
construing the same.
	 
	1.4	 	Purpose :






			
	          A    	 	The Agreement intends to expand upon the Initial Contract. Under the Agreement,
Biotecnol is assigned to complete the development according to the Programme of a
Process of IL13 to be transferred to a designated GMP manufacturing sub-contractor for
subsequent cGMP manufacturing. The Process shall be developed as stated into the
Programme, and according to the current good manufacturing practices (“cGMP”) and the
current good laboratory practices (“cGLP”) accepted by a “Regulatory Authority” (as
defined below) and in particular the following applicable regulatory
guidance documents :


1.4.1 FDA “Points to Consider in the Production and Testing of New Drugs and
Biologicals Produced by Recombinant DNA Technology” (1985)

1.4.2 FDA “Supplement to the Points to Consider in the Production and Testing of New
Drugs and Biologic & Produced by Recombinant DNA Technology: Nucleic Acid
Characterization and Genetic Stability” (1992)

1.4.3 EMEA “Production and Quality Control of Medicinal Products Derived by
Recombinant DNA Technology” (1995)






			
	          B    	 	IDM undertakes to let Biotecnol be in charge of the on-going management of the
outsourcing of manufacturing and release of Finished Product for renewable five years
period starting from the release of the first Finished Product batch.





 









 





			
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2. OBLIGATIONS OF BIOTECNOL





	 	 	Biotecnol shall undertake the work specified in the Programme and shall use its reasonable
endeavours to ensure that such work is undertaken in accordance with the time frames set out
in SCHEDULE 1 and with all appropriate necessary license. Outcome of the Programme shall be
considered in terms of (i) a Finished Product batch, (ii) a robust and
validation dependant, reproducible Process and all the documentation related as required by
the Regulatory Authority for registration and approvals of IDM Cell Drugsand iii) a master
validation plan
	 
	2.1	 	Upon IDM request, Biotecnol shall undertake to perform additional work described in Part 2 of
the Programme including comparability studies, formulation and filling of Product into
Finished Product, stability studies, implementation of the validation plan beyond the first
Finished Product batch and CMC section writing.
	 
	2.2	 	At IDM’s request, Biotecnol shall be in charge of the timely preparation of a dossier
containing the chemistry, manufacturing and control information (“CMC section”) for the IL-13
in accordance with 1.4.1, 1.4.2 and 1.4.3 for submission to the Regulatory Authority. The
Parties agree that the CMC section shall include existing stability studies results. Biotecnol
shall also be in charge of updating the CMC section to reflect changes or updates to the
Process. Biotecnol shall also be in charge of providing a timely response to any question on
the CMC section from Regulatory Authorities. IDM shall have an access and right to review the
CMC section as well as any responses to questions from Regulatory Authorities related to the
CMC section.
	 
	2.3	 	Biotecnol shall perform its obligations in accordance with all applicable laws and generally
accepted good scientific practice, provided that Biotecnol shall not be required hereby to
seek or acquire any certification from any Regulatory Authority that its facilities or
procedures comply with the good manufacturing practices or other standards thereof.
	 
	2.4	 	Biotecnol shall co-operate reasonably with IDM in undertaking the Programme in accordance
with this Agreement and shall act at all times in such a way as to further the objectives of
the Programme, provided that Biotecnol shall be under no obligation to comply with any
recommendations or instructions of IDM, unless otherwise required so to do by the Programme,
the Joint Management Committee or the Agreement.





	 	 	 	 	 
	2.5

	 	(a)
	 	Biotecnol shall ensure that the results of its work pursuant to the Programme are
recorded into laboratory notebooks. Such notebooks shall be recorded according to scientific
and intellectual property uses, such as but not limited to signature of each page by the
investigator undertaking such work, validation by competent authority and keeping in a safe
and secure place.
	 
	 	 	 	 
	 

	 	(b)
	 	Such notebooks and the contents thereof shall be the property of Biotecnol,
subject to IDM’s requirements regarding the filing, prosecution and maintenance of
Foreground Rights, although IDM shall, at its cost, be entitled on reasonable notice,
whether during or following the term of this Agreement, to inspect the same and to take
copies thereof.
	 
	 	 	 	 
	 

	 	(c)
	 	Biotecnol shall keep such notebooks and identify the same as containing the
results of its work pursuant to the Programme.






 









 






	2.6	 	Biotecnol shall, whether during or following the term of this Agreement, ensure that IDM has
reasonable access during working hours to all individuals involved in undertaking the
Programme for the purposes thereof, provided that such obligation shall cease in respect of
each such individual upon the termination of their employment by Biotecnol.
	 
	2.7	 	Biotecnol shall , according to the milestones defined on the Programme, and at the latest on
a quarterly basis, provide IDM with written reports of its progress in undertaking the
Programme.
	 
	2.8	 	Biotecnol will ensure that the Process shall be acceptable in terms of compliancy to the
guidelines of the Regulatory Authorities and third party’s Intellectual Property Rights.
	 
	 	 	During the Programme and the Manufacturing Period, Biotecnol shall ensure appropriate cGLP
or cGMP compliance either by internal resources or though appropriate consultancy whenever
the work is required to be carried out according to cGMP/cGLP.
	 
	2.9	 	During the Manufacturing Period, Biotecnol undertakes to oversee the manufacturing outsourcer
and sub-contractors to deliver in a timely manner at an agreed upon Transfer Price the batches
and or quantity of Finished Product according to IDM orders. Detailed terms and conditions
necessary to organise providing Finished Product to IDM shall be agreed upon in a
manufacturing agreement. The Parties agree to start negotiating upon initiation of the first
Finished Product batch.





3. OBLIGATIONS OF IDM





	3.1	 	IDM shall perform the work specified in the Programme to be undertaken by IDM and shall use
its reasonable endeavours to ensure that such work is undertaken in accordance with the time
frames set out therein.
	 
	3.2	 	IDM shall perform its obligations pursuant to clause 3.1 in accordance with all applicable
laws and generally accepted good scientific practices.
	 
	3.3	 	IDM shall co-operate reasonably with Biotecnol in undertaking the Programme in accordance
with this Agreement and shall act at all times in such a way as to further the objectives of
the Programme, provided that IDM shall be under no obligation to comply with any
recommendations or instructions of Biotecnol, unless otherwise required so to do by the
Programme, the Joint Management Committee or the Agreement.
	 
	3.4	 	IDM shall at its expense using reasonable efforts, deliver to Biotecnol, such of the IDM
Materials, the IDM Background Patents and the IDM Background Technology related to the
performance of the Programme as Biotecnol notifies IDM that it considers to be necessary for
Biotecnol to perform its obligations hereunder or as is otherwise specified in the Programme.
	 
	3.5	 	IDM shall render to Biotecnol without charge such technical assistance as Biotecnol may
request to interpret and explain any written information within those materials provided to
Biotecnol in accordance with clause 3.4 and as Biotecnol may otherwise reasonably require to
perform its obligations hereunder. Biotecnol undertakes not to consider IDM as Breaching Party
based on section 10.4 definition, because IDM (i) communicates information related to the
IL-13 development which interpretation is not certain, (ii) does not communicate information
related to the IL-13 development





 









 










			
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provided by IDM’s corporate partners.




3.6      IDM shall pay Biotecnol the fees specified in clause 4 for PART 1 of the Programme upon
Delivery. Upon IDM request of work specified in PART 2 of the Programme, the parties shall agree on
sub-contractors’ choice and financial support to be paid by IDM.




	3.7	 	Should IDM decide to complete the validation of the Process as required by the Regulatory
Authority, IDM will pay
	 
	 	 	•     the number of Finished Product batches in excess to the one indicated in the
Programme which total shall amount to the number of consecutive successful batches required
by the Regulatory Authority,
	 
	 	 	•     the work necessary for implementation of the validation master plan. In that case,
any additional Finished Product batch necessary to validate the Process shall in no case be
charged to IDM.





4. PAYMENT




IDM financial support to the PART 1 of the Programme, including an overall Programme success fee,
shall amount to [...***...] to be disbursed on a milestones and Go/NoGo decisions basis. Main steps
and milestones payments are included in SCHEDULE 2 and coded “TxPy” The financial support for PART
2 of the Programme should be negotiated in good faith by the parties.



IDM agrees to pay Biotecnol the following amounts:




	 	 	 	 	 
	Milestones

	 	Payment

related
	 	Definition
	 
	 	 	 	 
	 

	 	 [...***...] 
	 	upon execution of the LOI. Biotecnol hereby acknowledges that it
has already received such payment
	 
	 	 	 	 
	T1P1 

	 	[...***...]
	 	upon identification and confirmation of manufacturing facility
	 
	 	 	 	 
	T2P2 

	 	[...***...]
	 	upon successful processing of functional IL13 at 10mg/liter
according to the specifications defined in the Programme or agreed
upon by the Joint Management Committee. T2P2 Delivery will
trigger payments of: T4P2 and T5P2. Biotecnol hereby
acknowledges that it has already received such payment
	 
	 	 	 	 
	T3P1 

	 	[...***...]
	 	upon initiation of cell banking; Biotecnol hereby acknowledges
that it has already received such payment
	 
	 	 	 	 
	T3P2 

	 	[...***...]
	 	upon successful master and working cell bank production






	 	 	 	 	 
	 

	 	*
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under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 





	 	 	 	 	 
	T3P3

	 	[...***...]
	 	upon master and working cell bank release according to
specifications defined in the PROGRAMME or agreed upon by the
Joint Management Committee
	 
	 	 	 	 
	T4P1

	 	[...***...]
	 	upon initiation of process development fermentation. Biotecnol
hereby acknowledges that it has already received such payment
	 
	 	 	 	 
	T4P2

	 	[...***...]
	 	to pursue Process Development
Fermentation, Biotecnol hereby acknowledges that it has already received such payment
	 
	 	 	 	 
	T4P3

	 	[...***...]
	 	upon fermentation protocol finalization
	 
	 	 	 	 
	T4P4

	 	[...***...]
	 	upon report on reproducible laboratory fermentation process in
three batches at five (5) litres scale
	 
	 	 	 	 
	T5P 1

	 	[...***...]
	 	upon initiation of process development Down Stream Processing
(“DSP”). Biotecnol hereby acknowledges that it has already
received such payment
	 
	 	 	 	 
	T5P2

	 	[...***...]
	 	to pursue Process Development of DSP, Biotecnol hereby
acknowledges that it has already received such payment
	 
	 	 	 	 
	T5P3

	 	[...***...]
	 	upon final downstream processing protocol finalization
	 
	 	 	 	 
	T5P4

	 	[...***...]
	 	upon report on reproducible downstream process in three batches
at lab’s scale
	 
	 	 	 	 
	T6P1

	 	[...***...]
	 	upon initiation of analytical methods development. Biotecnol
hereby acknowledges that it has already received such payment
	 
	 	 	 	 
	T6P2

	 	[...***...]
	 	upon linked to SOP’s for process analysis and Product release
testing
	 
	 	 	 	 
	T6P3

	 	[...***...]
	 	upon a transfer of methods to sub-contractor for validation
	 
	 	 	 	 
	T6P4

	 	[...***...]
	 	upon report of completion of assays validation
	 
	 	 	 	 
	T7P1

	 	[...***...]
	 	upon initiation of process transfer
	 
	 	 	 	 
	T7P2

	 	[...***...]
	 	upon three successful lab scale runs demonstrating reproducible

process at sub-contractor
	 
	 	 	 	 
	T7P3

	 	[...***...]
	 	Upon successful pre-GMP pilot run, GMP process at large scaleof pilot plant allowing
for cGMP manufacturing meeting the specifications
defined during development work.






	 	 	 	 	 
	 

	 	*
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under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 





			
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	T7P4

	 	[...***...]
	 	upon successful audit of cGMP documentation prior to initiation
of cGMP manufacturing
	 
	 	 	 	 
	T9P1

	 	[...***...]
	 	upon initiation of first Product batch
	 
	 	 	 	 
	T9P2

	 	[...***...]
	 	upon release of first Product batch
	 
	 	 	 	 
	T10P1

	 	[...***...]
	 	The Programme success fee allowing to use the Finished Product
in Clinical trials, upon successful release of Finished
Product







	4.1	 	Shall Biotecnol fail to deliver to IDM the first Finished Product batch on the Date, due to
the non performance, fault or negligence from Biotecnol, , Biotecnol shall be liable of late
penalty payment. In the case of an Event of Force Majeure, then Biotecnol shall not be liable
for late penalty payment.
	 
	 	 	Such penalty payment shall amount to [...***...] per month of delay with a maximum not
exceeding [...***...] of total amount intended for the performance of the Programme (i.e.
total amount : [...***...]). Penalty payment shall be credited against future invoices.
	 
	 	 	Biotecnol shall not be subject to late penalty payment terms so long as the delay is the
consequence of IDM late decision or action .





Biotecnol shall not be subject to such penalty if it is shown that the late delivery by Biotecnol
did not affect IDMs ability to pursue their clinical trials program .



	 	 	 	 	 
	 

	 	*
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under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 






	4.3	 	IDM shall make all payments due pursuant to this clause 4 within twenty (20) days of
receipt of invoice. An invoice shall be paid by IDM only if the invoice is following a
Delivery .
	 
	4.4	 	Any payments due in accordance with this clause 4 but not paid on the due dates shall incur
interest at a rate of four (4%) percent above the lending rate from time to time of 3 M
EURIBOR, such interest to be compounded monthly.
	 
	4.5	 	The sums specified in this clause 4 as payable by IDM shall be exclusive of any due Value
Added Tax.
	 
	4.6	 	The price of IL-13 (“Transfer Price”) charged to IDM shall be the Cost of Goods of the IL-13
calculated annually on the basis of Biotecnol’s manufacturing expenses plus reasonable
allocations of sales and administrative overhead and a management fee not to exceed twenty
percent of the Costs of Good.
	 
	 	 	The “Cost of Goods” shall also include any payments or share of payment made by Biotecnol to
its direct and indirect licensors through multiple tiers of licenses that become due as a
result of the performance of this Agreement by Biotecnol or IDM. The Cost of Goods shall not
include any transportation insurance policy and related cost, which shall remain IDM’s.
Taxes if applicable and goods transportation cost are not included in the Cost of Goods but
subject to reimbursement by IDM.
	 
	 	 	Upon reasonable advance written notice, IDM shall have the right to audit the accounting
documents related to the Transfer Price during the Manufacturing Period at Biotecnol.
Detailed definition of Cost of Goods shall be agreed upon in the manufacturing agreement
referred to in section 2.10.
	 
	4.7	 	IDM may decide not to renew after the Manufacturing Period the outsourcing of manufacturing
and release of IL-13 to Biotecnol upon payment of cancellation fees. First termination notice
shall be communicated no later that than twelve (12) months prior to the end of the
Manufacturing Period. The amount of the cancellation fees shall be agreed upon in good faith
by the Parties and shall not exceed the management fee of one Finished Product batch. This
amount shall decrease by twenty (20) percent per year following the end of the Manufacturing
Period.





 









 





			
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5. PROGRAMME MANAGEMENT




	 	 	 	 	 
	5.1

	 	(a)
	 	Following the Effective Date, the parties shall form a joint management committee (the
“Joint Management Committee”), which shall be responsible for promoting the co-operation of
the parties in accordance with this Agreement and in particular but without limitation for
assisting each party in:







	 	(i)	 	monitoring and evaluating its progress in undertaking the Programme;
	 
	 	(ii)	 	reporting such progress to the other party;
	 
	 	(iii)	 	co-ordinating the parties’ co-operation in advancing the Programme; and
	 
	 	(iv)	 	proposing timelines in respect of advancing the
Programme and possibly modifying/updating the Programme
	 
	 	(v)	 	agreeing on the completion of milestones and in particular
Delivery linked to payments as defined in clause 4
	 
	 	(vi)	 	agreeing on the choice of outsourcing company for cGMP, Cell
Banking, Quality Control development, Quality Control testing etc... based on
expertise, risk assessment, timing and pricing.





	 	 	 	 	 
	5.2

	 	(a)
	 	The Joint Management Committee shall comprise three (3) core representatives of each
party, who shall each be an employee, officer or consultant of the party which they represent.
IDM’s representatives shall be the Director, Business Expansion, the Director Manufacturing
and the Director Quality System. Biotecnol’s representatives shall be the Chief Scientific
Officer, the Chief Operating Officer and the Development Manager .
	 
	 	 	 	 
	 

	 	 	 	Other persons, including but not limited to regulatory representative will be asked to
contribute on an adhoc basis.
	 
	 	 	 	 
	 

	 	(b)
	 	All members of the Joint Management Committee shall have an ongoing familiarity
with the Programme and appropriate knowledge having regard to the Joint Management
Committee’s responsibilities.
	 
	 	 	 	 
	5.3

	 	 	 	Each party may replace those core members of the Joint Management Committee which it has
appointed at will and at any time upon written notice to the other party.
	 
	 	 	 	 
	5.4

	 	(a)
	 	The Joint Management Committee shall meet as frequently as it chooses but in any event no
less often than once every twenty (20) Business Days.
	 
	 	 	 	 
	 

	 	(b)
	 	The Joint Management Committee shall meet either by telephone conference call or in
person, provided that where the Joint Management Committee meets in person, such meetings
shall alternate between the parties’ respective principal places of business or such
other locations as the Joint Management Committee may agree.
	 
	 	 	 	 
	 

	 	(c)
	 	All meetings of the Joint Management Committee shall be conducted in English or
such






 









 




	 	 	 	 	 
	 	 	other language as the Joint Management Committee may unanimously agree.
	 
	 	 	 	 
	 

	 	(d)
	 	The quorum for any key decision of the Joint Management Committee to be valid
shall be of at least one (1) core member appointed by each of the parties
	 
	 	 	 	 
	 

	 	(e)
	 	In the event that both parties consent, third parties may attend meetings of
the Joint Management Committee as observers, provided that such representatives are
subject to binding obligations of confidentiality in favour of the parties at least as
restrictive as those in this Agreement.
	 
	 	 	 	 
	 

	 	(f)
	 	Each party shall bear its own costs in connection with meetings of the Joint
Management Committee.
	 
	 	 	 	 
	 

	 	(e)
	 	Joint Management Committee minutes shall be draft by each party alternatively
no later than five (5) Business Days after the meeting. The non-drafting party shall
comment within five (5) Business Days so as to communicate the final Joint Management
Committee minutes within ten (10) Business Days to interested persons at each party.






	5.5	 	Each party shall provide all reasonable assistance to the Joint Management Committee in
assisting the Joint Management Committee to execute its responsibilities hereunder.
	 
	5.6	 	The Joint Management Committee shall have no authority to require either party to take or to
refrain from taking any particular steps or other action, provided that this clause 5.6 shall
not operate to exempt either party from fulfilling its obligations pursuant to this Agreement
or the Programme.
	 
	5.7	 	If the Joint Management Committee members disagree as to whether any and/or what steps should
be taken during the Programme, either party may within twenty (20) days of such disagreement
refer the disagreement to the President of IDM and the CEO of Biotecnol. In the event that
within forty (40) days of referral to the President & CEO of IDM and the CEO of Biotecnol the
Parties have failed to resolve the disagreement, either Party may refer the disagreement to
arbitration in Belgium who shall appoint an expert to determine the dispute (the “Expert”).
The decision of the Expert, who shall act as expert and not as arbitrator shall be final and
binding on the Parties. The costs of the Expert shall be shared equally.





6.  SUB-CONTRACTING AND OUTSOURCING






6.1        Principles to be applied by Biotecnol during the Programme and the Manufacturing Period:


6.1.1      Biotecnol shall in all circumstances remain liable to IDM with regard to any part of the
Programme or Process it decided to sub-contract to third parties.


6.1.2      Outsourcing and sub-contracting agreements shall comply with the terms and conditions set
forth herein.


6.1.3      Biotecnol undertakes in its name and on behalf of its outsourcers or sub-contractors to
cooperate with IDM if inspections by health authorities are required with respect to Product,
Finished Product and Process.


6.1.4      Upon reasonable advance written notice, IDM shall have the right to inspect the facilities
and the means used to perform the Programme or the Process and later on during the Manufacturing
Period at Biotecnol and/or chosen sub-contractors or outsourcers to ensure that the Programme or
the Process is carried out in accordance with cGMP, cGLP, rules and regulations, whenever the work
needs to be carried out according to the said cGMP, cGLP, rules and regulations.


 









 





			
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	 	6.1.5	 	Biotecnol, its sub-contractors and out-sourcers shall be held liable for any
default in supply, such as but not limited to contamination issue that may arise during
the Programme and the Manufacturing Period. IDM shall not be bound to financial
compensation in excess of the agreed upon Programme fees and Transfer Price.
	 
	 	6.1.6	 	Regarding any outsourcing and sub-contracting agreements, Biotecnol shall
negotiate that






	 	(a)	 	in case of early termination of the Agreement,
	 
	 	(b)	 	in case of expiration of the Agreement,
	 
	 	(c)	 	in case of Biotecnol’s bankruptcy, then






IDM shall be entitled, at no costs and at its sole discretion, to substitute itself to
Biotecnol vis-à-vis the outsourcing and sub-contracting party.




	6.2	 	Principles specific to the Programme performance :






	 	6.2.1	 	Biotecnol is not authorised to sub-contract or out-source the performance of
its obligations pursuant to clause 2.1 unless otherwise specified in the Programme, the
Agreement or authorised by the Joint Management Committee.
	 
	 	6.2.2	 	However, IDM will allow Biotecnol to outsource or sub-contract activities
such as Cell Banking, QC development, QC testing. Choices of sub-contractors or
outsourcers shall be agreed upon in accordance with section 5.1 (vi).
	 
	 	6.2.3	 	During the performance of the Programme, Biotecnol shall be bound by late
delivery penalties as defined in Clause 4.2 even though the delay is due to Biotecnol’s
sub-contractors.






	6.3	 	Principles specific to the Manufacturing Period :






	 	-	 	Biotecnol undertakes that it shall take all reasonable means to sustain
continued manufacturing capabilities during the Manufacturing Period.
	 
	 	-	 	Biotecnol is not authorized to substitute any sub-contractor or out-sourcer in
charge of part or all of the Process, which have been agreed upon during the Programme
performance by the Joint Management Committee without prior adequate notice and
authorization by IDM.
	 
	 	-	 	The Parties evaluate the time for transferring the Process at 18 (eighteen)
months. As a consequence the production agreement signed by the sub-contractor or
out-sourcer and Biotecnol shall provide that:






	 	•	 	in the case where said production agreement is terminated, expired or
assigned, then IDM or any other person IDM may decide, shall benefit from
the production agreement rights and obligations
	 
	 	•	 	any without cause termination shall be given eighteen (18) months in
advance to ensure manufacturing continuity.





 









 





7. INTELLECTUAL PROPERTY RIGHTS




	 	 	 	 	 
	7.1

	 	(a)
	 	Subject as expressly provided in clause 7.5, Biotecnol is and shall remain the sole
owner or the licensee, as applicable, of all Intellectual Property Rights in the Biotecnol
Background Patents and Biotecnol Background Technology.






         (b)    Subject as expressly provided in clause 7.3, IDM is and shall remain the sole owner or
licensee, as applicable, of all Intellectual Property Rights in the IDM Materials, the IDM
Background Technology and the IDM Background Patents and the Programme Materials.




	7.2	 	IDM acknowledges and agrees to the findings and recommendations contained in the preliminary
Biotecnol’s study of the freedom to operate received On November 28, 2002 which drove some
technical choices of the Process. However during the development of the Process, Biotecnol
will take appropriate measures to verify that the Process developed for IL-13 production and
commercialisation is not dependant upon third parties intellectual property rights and will
keep IDM informed, through a study update, of this verification before executing the milestone
of transfer to pilot facility (T7P1). In case of such dependence, Biotecnol will negotiate the
license agreement required, and provide IDM or any third party IDM shall require, with the
opportunity to be assigned in cases described below. In all cases where a license is to be
negotiated by Biotecnol, IDM shall be informed and will be given a reasonable opportunity to
comment on or discuss the proposal.






     With regard to the above, Biotecnol shall negotiate that in case of early termination,
expiration of the Agreement, in case of Biotecnol’s bankruptcy then :




	 	(a)	 	IDM shall be entitled, at no costs and at its sole discretion, to substitute to
Biotecnol itself or its affiliated, merging or acquiring company vis-à-vis the
licensing party.
	 
	 	(b)	 	IDM shall remain the sole owner of all Foreground Rights.






	7.3	 	IDM hereby grants Biotecnol a non-exclusive royalty-free licence to use any and all IDM
Materials, IDM Background Technology and IDM Background Patents disclosed or otherwise
provided or available to Biotecnol pursuant to this Agreement or otherwise, for the purpose of
permitting and assisting Biotecnol in performing its obligations under the scope of the
Agreement and exercising it rights pursuant hereto.
	 
	7.4	 	Foreground Rights shall be jointly owned by the Parties.





Biotecnol shall promptly notify IDM, in writing, of any Foreground Rights conceived and/or reduced
to practice during the term of the Agreement. If the parties deem it appropriate that a patent
application be filed in respect of such Foreground Rights, IDM shall be responsible for and share
with Biotecnol all costs incurred in connection with the preparation, filing, prosecution and
maintenance of European and foreign patent applications. Biotecnol and IDM agree to negotiate in a
co-ownership agreement the percentage of patent ownership in good faith and to apply said
percentage to the sharing of costs related. Biotecnol



 









 





			
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shall be given an opportunity to review and provide input into the scope and content of any such
preparation, filing and prosecution. IDM shall supply Biotecnol with copies of main documents
received or filed in connection with the prosecution of such patents in sufficient time so as to
provide Biotecnol an opportunity to comment thereon, as the case may be.





If IDM, for any reason, declines responsibility for any such patent or patent application,
it shall provide reasonable prior written notice to Biotecnol of such abandonment or
decline of responsibility within at least thirty (30) Business Days from any office action
to be decided.




In such an event, Biotecnol shall have the right, at its expense, to prepare, file,
prosecute and maintain such patent rights, without divesting IDM from its rights described
hereof.




The parties agree that neither parry shall be entitled to license or assign in any way its
part of patent ownership to third parties without the other party’s agreement, which shall
not be unreasonably withheld. If, pursuant to the Agreement, any party licenses any
Foreground Rights to any third party, it shall reimburse on third party’s income the other
party for all reasonable attorney fees and costs paid as a result of the prosecution,
preparation, filing and maintenance of such Foreground Rights.




	7.5	 	Biotecnol hereby grants IDM a payment-free non-cancelable worldwide exclusive license solely
for the “Field” (including the right to grant sub-licences thereunder) of its share in respect
of the Foreground Rights and shall grant a licence on like terms under any patent which IDM
obtains pursuant to clause 7.3 (for the purposes of this clause 7, a “Patent”), in all the
countries in which such patent protection is obtained, for the full duration of such Patent.
Should the Foreground Rights be used or licensed by Biotecnol to manufacture IL-13 for use
outside of the Field, subject to Sanofi-Synthelabo S.A.’s approval — or from Sanofi
Synthelabo’s Affiliates’ approval, a royalty compensation or a fixed payment to IDM shall be
due to IDM. For the sake of clarity and avoidance of doubt the choice between receiving a
royalty compensation or a fixed payment will be at IDM’s sole discretion, and in either way
will be negotiated in good faith between the parties.





	 	 	 	 	 
	7.6

	 	(a)
	 	Each party shall inform the other party of any infringement or suspected infringement of
any Patent forthwith upon such infringement or suspected infringement coming to its notice and
shall provide such other party with full particulars thereof.
	 
	 	 	 	 
	 

	 	(b)
	 	If either party becomes aware that any other person alleges that any Patent
is invalid or that the use of any Foreground Rights infringes any rights of another
party or that any such Patent is otherwise attacked or attackable by a third party, it
shall immediately give the other party full particulars in writing thereof and shall
make no comment or admission to any third party in respect thereof.
	 
	 	 	 	 
	7.7

	 	(a)
	 	Both Biotecnol and IDM shall have the conduct of all judiciary proceedings relating to
any Patents and shall jointly decide what action if any to take in respect of any infringement
or alleged infringement thereof or any other claim or counterclaim brought or threatened in
respect of the use or registration thereof.






 









 





          (b) Notwithstanding the foregoing, in the event of any infringement or alleged infringement of
any Patent and in the event that either party chooses not to pursue the infringer or alleged
infringer thereof, the other party may take all legitimate steps to halt any such infringement and
the abandoning party shall, at the other party’s expense, provide all reasonable assistance to such
other party, (including without limitation the use of its name in or being joined as a party to
proceedings) in connection with such steps.




	7.8	 	Nothing in this Agreement shall give or grant to either party any right in any trademark,
patent or other Intellectual Property Right of the other party expect as specifically provided
herein.





8. CONFIDENTIALITY





	8.1	 	Each party shall, during the full term of this Agreement and thereafter, keep secret and
confidential the contents of this Agreement and all Confidential Information of the other
party and shall not use or disclose the same to any person, save to the extent necessary to
perform its obligations pursuant to this Agreement in accordance with its terms or save as
expressly authorised in writing to be disclosed by the other party.
	 
	8.2	 	The obligation of confidentiality contained in clause 8.1 shall not apply or (as the case may
be) shall cease to apply to details of the contents of this Agreement or to Confidential
Information which:






	 	(a)	 	at the time of its disclosure by the disclosing parry is already in the public
domain or which subsequently enters the public domain other than by breach of the terms
of this agreement by the receiving party;
	 
	 	(b)	 	is already known to the receiving parry (as evidenced by written records) at
the time of its disclosure by the disclosing party and was not otherwise acquired by
the receiving party from the disclosing party under any obligations of confidence;
	 
	 	(c)	 	is at any time after the date of this Agreement acquired by the receiving party
from a third party having the right to disclose the same to the receiving party without
breach of obligation owed by that third party to the disclosing party; or
	 
	 	(d)	 	is required to be disclosed by applicable law or order of a court of competent
jurisdiction or government department or agency or the rules and requirements of any
other regulatory body, provided that prior to such disclosure the receiving party shall
advise the disclosing party of the proposed form of the disclosure.






	8.3	 	Notwithstanding the foregoing, each parry may disclose Confidential Information of the other
party and details of the contents of this Agreement to its professional advisors, and for IDM
to Sanofi-Synthelabo S.A. or Sanofi-Synthelabo S.A.’s Affiliates provided that they are
subject to obligations of confidentiality at least as restrictive as those herein and the
parties may disclose:






	 	(a)	 	the existence of this Agreement to its actual or potential financial backers
for the purposes of seeking or obtaining finance therefrom; and





 









 





			
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	 	(b)	 	the scope of the Programme for the procurement of subcontractors for pursuing
any work according to cGMP or cGLP and thus for obtaining quotes;
	 
	 	(c)	 	in the event that IDM needs to use technology belonging to third parties,
Biotecnol can disclose to its licensors any rights sub-licensed to IDM thereunder,
IDM’s identity, the Effective Date, the definition[s] of “Field”, “Finished Product”
and “Product(s)” and such other terms defined herein as are necessary to understand
[its][their] meaning, and the scope of the licence granted hereunder.






	8.4	 	Each party shall procure that all its employees, contractors, consultants, advisers and
sub-licensees pursuant to this agreement (if any) who have access to any information of the
other to which the obligations of clause 8.1 apply shall be made aware of and subject to these
obligations and shall further procure that so far as is reasonably practicable, all such
employees, contractors and sub-licensees shall enter into undertakings in favour of the other
party to this end.





9. WARRANTIES AND DISCLAIMER





	9.1	 	Biotecnol warrants that as far as it is aware after making due and careful enquiry, that the
use of the Biotecnol Background Technology and the Biotecnol Background Patents in the
Programme and during the Manufacturing Period as contemplated in this Agreement, the Process
for production of the Product and the Finished Product, will not constitute an infringement of
any Intellectual Property Rights of any third party.
	 
	9.2	 	To IDM’s best knowledge, the use of part or all of IDM Background Technology in connection
with the Programme as contemplated herein does not conflict with, misappropriate, or infringe
the intellectual property rights of any third party. Furthermore IDM warrants that it has
secured a non-exclusive licence for the use, development and manufacturing of IL-13 in the
Field and is therefore allowed to subcontract Biotecnol to perform the Programme.
	 
	9.3	 	Each party warrants to the other that it is not party to and shall not enter into any
agreement, arrangement, understanding or negotiations with any third party, which prevent it
entering into or performing its obligations hereunder, and that it is a duly organised and
validly existing corporation in good standing under the laws of its own jurisdiction.
	 
	9.4	 	Nothing contained in this Agreement shall be construed as a warranty by Biotecnol that any
Products or Finished Product will be suitable for any particular purpose, including without
limitation, for therapeutic or other use in humans, expect for the intended use in the Field.
	 
	9.5	 	Subject to clause 9.6, neither party shall be liable to the other under or in connection with
this Agreement, whether in contract, tort (including negligence), misrepresentation (other
than where made fraudulently), breach of statutory duty or otherwise for any:





(a) loss of business, contracts, profits, anticipated savings, goodwill, or revenue; or



(b) indirect or consequential loss whatsoever incurred by the other, or any of its Affiliates,
whether or not such other party was advised in advance of the possibility of any such loss.



 









 






	9.6	 	Nothing in this Agreement shall limit either party’s liability in respect of:






	 	(a)	 	any claim for death or personal injury caused by its negligence or that of its
employees, contractors or agents; or
	 
	 	(b)	 	any other liability which may not be limited or excluded at law.






	10.	 	DURATION AND TERMINATION
	 
	10.1	 	This Agreement shall enter into force on the Effective Date and unless terminated as provided
herein, shall remain in force not before the end of the Manufacturing Period.
	 
	10.2	 	The Parties agree that the Joint Management Committee may recommend to stop the Programme at






	 	•	 	the end of stage T2 if IL-13 is not functional according to the
specifications defined in the Programme or agreed upon by the Joint Management
Committee and/or
	 
	 	•	 	the end of stage T5 if the process is not reproducible according to the
specifications defined in the Programme or agreed upon by the Joint Management
Committee and/or
	 
	 	•	 	if the yield is not amounting to [...***...] and/or
	 
	 	•	 	before the manufacturing of the first Product batch is initiated (T9).





Either Party shall be entitled to terminate the Agreement based on the Joint Management Committee
meeting minutes. The terminating Party undertakes to decide within thirty (30) Business Days from
the Joint Management Committee meeting minutes issuance. The terminating Party shall within twenty
(20) Business Days of the termination notice receipt set-up a meeting between the President & CEO
of IDM and the CEO of Biotecnol to detail the consequences of such termination, in particular
define the non-cancellable costs incurred by either Party and costs subject to reimbursement by
either Party . In the event that within forty (40) days of referral to the President & CEO of IDM
and the CEO of Biotecnol the Parties have failed to resolve the indemnification issue, either Party
may refer the disagreement to arbitration in Belgium who shall appoint an expert to determine the
dispute (the “Expert”). The decision of the Expert, who shall act as expert and not as arbitrator
shall be final and binding on the Parties. The costs of the Expert shall be shared equally.



The parties agree that IDM shall be entitled to notify the termination of the Agreement at any time
during the Manufacturing Period if [...***...].




	10.3	 	During the Manufacturing Period, IDM shall not be allowed to terminate the Agreement but
within the terms agreed upon in section 4.7. Biotecnol shall be entitled to terminate the
Process performance at any time with an eighteen (18) months prior notice to IDM.






	10.4	 	A party (the “Initiating Party”) may terminate this agreement with immediate effect by written
notice to the other party (the “Breaching Party”) on or at any time after the occurrence of
any of the





	 	 	 	 	 
	 

	 	*
	 	Confidential Treatment Requested

under 17 C.F.R. §§ 200.80(b)(4) and

240.24b-2(b)(1)






 









 





			
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following events:




	 	(a)	 	the Breaching Party being in breach of a material obligation under this
agreement and, if the breach is capable of remedy, failing to remedy the breach within
ten (10) Business Days starting on the Business Day after receipt of written notice
from the Initiating Party giving full details of the breach and requiring the Breaching
Party to remedy the breach;
	 
	 	(b)	 	the Breaching Party passing a resolution for its winding-up or a court of
competent jurisdiction making an order for the Breaching Party’s winding-up or
dissolution;
	 
	 	(c)	 	the making of an administration order in relation to the Breaching Party or the
appointment of a receiver over, or an encumbrancer taking possession of or selling, an
asset of the Breaching Party;
	 
	 	(d)	 	the Breaching Party making an arrangement or composition with its creditors
generally or making an application to a court of competent jurisdiction for protection
from its creditors generally; and






	10.5	 	For the purpose of clause 10.4 (a) above, a breach will be considered capable of remedy if
time is not of the essence in performance of the obligation in question and if the Breaching
Party can comply with the obligation within the ten (10) Business Day period referred to in
clause 10.4(a).





11. EFFECT OF TERMINATION





	11.1	 	Upon the termination or expiry of this Agreement, each party shall at the instruction of the
other, either destroy or return all Confidential Information of the other and in particular:






	 	(a)	 	Biotecnol shall at the instruction of IDM, either destroy or return all
quantities of IDM Background Technology and IDM Materials remaining in its possession;
and
	 
	 	(b)	 	IDM shall at the instruction of Biotecnol, destroy or return all quantities of
Biotecnol Background Technology remaining in its possession.






	11.2	 	In cases detailed in the section 10.4 b, c or d and in the case where Biotecnol is the
Breaching Party in section 10.4 a, the remaining party shall be entitled to full ownership on
Foreground Rights issuing from the last milestone payment.
	 
	11.3	 	The provisions of clause 11.1 shall be subject to the rights of IDM pursuant to clause 7.5,
such that IDM may retain such Confidential Information as is necessary for it the exploit the
licence granted thereby.





11.4 The termination of this Agreement shall be without prejudice to the rights and obligations of
the parties provided in clauses 1, 4, 7, 8, 9, 10, 11 and 20, all of which shall survive such
termination and shall be without prejudice to any accrued claims or rights of action that either
party may have against the other up to the date of such termination.



11.5 For the purpose of clause 10.4 (b), 10.4 (c) and 10.4 (d), if IDM is the Breaching Party,
Biotecnol agree to offer the Sanofi- Synthelabo group an option to be assigned the rights and
obligations of IDM under the Agreement.



12. FORCE MAJEURE




 









 





12.1 “Event of Force Majeure” means, in relation to either party, an event or circumstance beyond
the reasonable control of that party (the “Claiming Party”) including, without limitation, (whether
or not by the Claiming Party), strikes, lock-outs and other industrial disputes (in each case,
whether or not



relating to the Claiming Party’s workforce) which renders the performance of the obligation of that
party not commercially or technically possible.



12.2 The Claiming Party shall not be deemed to be in breach of this Agreement or otherwise liable
to the other party (the “Non-Claiming Party”) for any delay in performance or any non-performance
of any obligations under this Agreement (and the time for performance shall be extended
accordingly) to the extent that the delay or non-performance is due to an Event of Force Majeure
provided that:




	 	(a)	 	the Claiming Party could not have avoided the effect of the Event of Force
Majeure by taking precautions which, having regard to all matters known to it before
the occurrence of the Event of Force Majeure and all relevant factors, it ought
reasonably to have taken but did not take; and
	 
	 	(b)	 	the Claiming Party has used reasonable endeavours to mitigate the effect of the
Event of Force Majeure and to carry out its obligations under this Agreement in any
other way that is reasonably practicable.





12.3 The Claiming Party shall promptly notify the Non-Claiming Party of the nature and extent of
the circumstances giving rise to the Event of Force Majeure




	12.4	 	If the Event of Force Majeure in question prevails for a continuous period in excess of three
(3) months after the date on which it began, the Non-Claiming Party may give notice to the
Claiming Party terminating this Agreement. The notice to terminate must specify the
termination date, which must not be less than thirty (30) clear days after the date on which
the notice to terminate is given. Once the notice to terminate has been validly given, this
Agreement will terminate on the termination date set out in the notice. Neither party shall
have any liability to the other in respect of termination of this Agreement due to an Event of
Force Majeure. In such circumstances, section 11.4 conditions shall apply





13. COSTS




Save as expressly otherwise provided in this Agreement each of the parties shall bear its own
legal, accountancy and other costs, charges and expenses connected with the negotiation,
preparation and implementation of this Agreement and any other agreement incidental to or referred
to in this Agreement.



14. VARIATIONS




This Agreement may be varied only by a document signed by each of the parties.



15. WAIVER





	15.1	 	A waiver of any term, provision or condition of, or consent granted under, this Agreement
shall be effective only if given in writing and signed by the waiving or consenting party and
then only in the





 









 





			
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	 	 	instance and for the purpose for which it is given.
	 
	15.2	 	No failure or delay on the part of any party in exercising any right, power or privilege
under this Agreement shall operate as a waiver thereof, nor shall any single or partial
exercise of any such right, power or privilege preclude any other or further exercise thereof
or the exercise of any other right, power or privilege.
	 
	15.3	 	No breach of any provision of this Agreement shall be waived or discharged except with the
express written consent of the parties.
	 
	15.4	 	The rights and remedies herein provided are cumulative with and not exclusive of any rights
or remedies provided by law.
	 
	16.	 	INVALIDITY





If any provision of this Agreement is or becomes (whether or not pursuant to any judgment or
otherwise) invalid, illegal or unenforceable in any respect under the law of any jurisdiction:




	 	(a)	 	the validity, legality and enforceability under the law of that jurisdiction of
any other provision; and
	 
	 	(b)	 	the validity, legality and enforceability under the law of any other
jurisdiction of that or any other provision,






shall not be affected or impaired in any way thereby.



17. NOTICES





	17.1	 	Any notice, demand or other communication given or made under or in connection with the
matters contemplated by this agreement shall be in writing and shall be delivered personally
or sent by fax or prepaid internationally recognised courier (e.g. DHL, FedEX), except when
otherwise indicated.





	 	 	 
	In case of Biotecnol to:
	 

	 	Taguspark
	 

	 	Edificio Inovacao IV N° 809
	 

	 	2780-920 Oeiras
	 

	 	Portugal
	 

	 	Attention: CEO
	 

	 	Fax: +351 21 422 0529






	 	 	 
	In case of IDM to:
	 

	 	172 rue de Charonne
	 

	 	75545 Paris Cedex 11
	 

	 	France
	 

	 	Attention: President & CEO
	 

	 	Fax: +33 (0)1 40 090 425






and shall be deemed to have been duly given or made as follows:




	 	(a)	 	if personally delivered, upon delivery at the address of the relevant party;





 









 






	 	(b)	 	if sent by an internationally recognised courier (e.g. DHL, FedEX), two
Business Days after the date of posting;
	 
	 	(c)	 	if sent by air mail, five (5) Business Days after the date of posting; and
	 
	 	(d)	 	if sent by fax, one Business Days after the date of sending;





provided that if, in accordance with the above provision, any such notice, demand or other
communication would otherwise be deemed to be given or made after 5.00 p.m. local time such notice,
demand or other communication shall be deemed to be given or made at the start of working hours on
the next Business Day.




	17.2	 	A party may notify the other party to this Agreement of a change to its name, relevant
addressee, address or fax number for the purposes of clause 17.1, provided that such
notification shall only be effective on:






	 	(a)	 	the date specified in the notification as the date on which the change is to
take place; or
	 
	 	(b)	 	if no date is specified or the date specified is less than five (5) Business
Days after the date on which notice is given, the date falling five (5) Business Days
after notice of any such change has been given.






 










 







			
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	18.	 	NO PARTNERSHIP
	 
	18.1	 	Nothing in this Agreement and no action taken by the parties pursuant to this Agreement shall
constitute, or be deemed to constitute, the parties a partnership, association, joint venture
or other co-operative entity.




18.2 At no time shall either of the parties have the authority to hold itself out as the agent of
the other or as being empowered to bind the other in any way whether contractually or otherwise.





	19.	 	ASSIGNMENT




Neither party may, without the prior written consent of the other, assign the benefit of all or any
other party’s obligations under this Agreement, nor any benefit arising under or out of this
Agreement, provided that each party may assign or otherwise transfer this Agreement, or the
interests hereunder, by operation of law or otherwise without the consent of the other party:





	 	•	 	to any of its Affiliates or
	 
	 	•	 	to any other person with which such party may merge, consolidate or transfer all or
substantially all of such Party’s assets related to the Product, Finished Product or
Process.




This Agreement and each party’s rights and obligations hereunder shall inure to the benefit of, and
be binding upon, the permitted successors and assigns of the parties hereto; provided, that
any assignment in violation of this section shall be null and void.





	20.	 	GOVERNING LAW AND JURISDICTION
	 
	20.1	 	This Agreement (and any dispute, controversy, proceedings or claims of whatever nature
arising out of or in any way relating to this Agreement or its formation) shall be governed by
and construed in accordance with Belgium law.
	 
	20.2	 	Each of the parties to this Agreement irrevocably agrees that any dispute arising out of or
in connection with this Agreement shall be settle by arbitration, except for the settlement
described in section 5.8, where an Expert shall file a binding decision. Such arbitration
shall be held in English in accordance with the rules of Cepani (Centre Belge pour l’Etude et
la Pratique de l’Arbitrage National et International) by a three arbitrators appointed in
accordance with such rules. The place of arbitration shall be Brussels. Language of
arbitration shall be English.
	 
	 	 	The arbitrators shall be appointed by agreement between the parties or failing agreement
within a period of twenty one (21) Business Days shall be appointed at the request of any
party by the Secretary-General for the time being of CEPANI. So far as possible the decision
of the arbitrators shall be given within twenty one (21) Business Days of their appointment
and shall be final and binding on the parties who renounce any right of appeal against such
arbitration award.
	 
	21.	 	ENTIRE AGREEMENT
	 
	21.1	 	Subject to clause 21.2, this Agreement constitutes the entire and only agreement between the
parties relating to the subject matter hereof and neither party has been induced to enter into
this Agreement in reliance upon, nor has any such party been given, any warranty,
representation, statement, assurance, covenant, agreement, undertaking, indemnity or
commitment of any nature whatsoever other than as are expressly set out herein and, to the
extent that any of them has been, it unconditionally and irrevocably waives any claims, rights or remedies which any of
them might otherwise have had in relation thereto.




 









 











			
	Confidential
	 	13-Nov-03





21.2 The provisions of this clause 21 shall not exclude any liability which either party would
otherwise have to the other party or any right which either of them may have in respect of any
statements made fraudulently by either of them prior to the execution of this Agreement or any
rights which either of them may have in respect of fraudulent concealment by the other.



21.3 All schedules are integral part of this Agreement.



IN WITNESS whereof this agreement has been executed on the date first above written.




Signed by

for and on behalf of Biotecnol SA




	 	 	 
	/s/ Pedro de Noronha Pissara

	 	/s/ Luis Amado
	CEO

	 	COO
	 
	 	 
	 
	 	 
	Signed by
	 	 
	for and on behalf of IDM SA
	 	 
	 
	 	 
	/s/ Jean-Loup Romet-Lemonne
	 	 
	President & CEO
	 	 






 









 





			
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	 	13-Nov-03






SCHEDULE 1




PROGRAMME




 





Process development and cGMP production of clinical grade Interleukin 13 (IL-13) for ex-vivo
cell therapy. Revised outline of Work Program



 




Biotecnol SA




Taguspark

Edificio Inovacâo IV, 809

Porto Salvo

2780-920 Oeiras

Portugal

www.biotecnol.com



Contact: Philip Cunnah, Ph.D.

Tel: +21-4220520

Fax: +21-4220529

Email: pjc@biotecnol.com




 









 








			
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	 	13-Nov-03






	 	 	 	 	 
	1. INTRODUCTION 
	 	 	3	 
	 
	 	 	 	 
	2. OBJECTIVES 
	 	 	4	 
	 
	 	 	 	 
	3. THE APPROACH 
	 	 	5	 
	 
	 	 	 	 
	4. WORK PROGRAM 
	 	 	6	 
	 
	 	 	 	 
	T1 IDENTIFICATION OF MANUFACTURING FACILITY 
	 	 	6	 
	 
	 	 	 	 
	T2
PRODUCTION OF IL13 FROM BIOTECNOL’S PR EXPRESSION SYSTEM 
	 	 	7	 
	 
	 	 	 	 
	T3 CELL BANKING 
	 	 	8	 
	 
	 	 	 	 
	T4 PROCESS DEVELOPMENT — FERMENTATION 
	 	 	9	 
	 
	 	 	 	 
	T5 PROCESS DEVELOPMENT: DSP 
	 	 	12	 
	 
	 	 	 	 
	T6 DEVELOPMENT OF ANALYTICAL METHODS FOR PROCESS MONITORING, AND LOT RELEASE TESTING
	 	 	18	 
	 
	 	 	 	 
	T7 PROCESS TRANSFER TO CGMP FACILITY 
	 	 	23	 
	 
	 	 	 	 
	T9 CGMP BATCH PRODUCTION AND ANALYSIS 
	 	 	25	 
	 
	 	 	 	 
	PART II 
	 	 	26	 
	 
	 	 	 	 
	T1O FILLING AND FINISHING OF PRODUCT TO DELIVER FINISHED PRODUCT 
	 	 	26	 
	 
	 	 	 	 
	T11 GENERATION OF PRELIMINARY DATA TO DEMONSTRATE PRODUCT STABILITY 
	 	 	27	 
	 
	 	 	 	 
	T12 STABILITY STUDIES ON CGMP GRADE PRODUCT AND FINISHED PRODUCT
	 	 	29	 







 










 








1. Introduction




In a previous Prototype Production Contract between Biotecnol SA and Immuno-Designed
Molecules (IDM), Biotecnol had the objective to provide triplicate samples of pharmaceutical
grade IL-13 having the same bioactivity as the standard provided to IDM by Sanofi-Synthelabo.
Accordingly clause 1, clauses 2.1 to 2.3 of that contract ,dated of March 8th 2001, was
successfully accomplished.



Furthermore according to clause 2.4, Biotecnol would evaluate the best system for producing a
soluble form of IL13 according to the specifications set. Biotecnol has provided solid evidence
that due to the properties of the molecule, soluble production could not be achieved despite
the large variety of systems used. The fact that IL-13 could only be produced in inclusion
bodies was later on confirmed by Sanofi-Synthelabo’s report 8th November 2001.



Biotecnol quickly moved on to consider inclusion bodies for production of the molecule and
using it’s proprietary technology a functional prototype was developed. The systems selected
for insoluble expression were the BT Xanthosine Expression System and the pL-pR / ant system.
Fermentation process was developed and a downstream processing methodology was applied to
production of samples in the laboratory. Biotecnol compiled a report in which these
methodologies were described, (Process Description — Production of rHIL13 in E.coli, February
2002.



In a meeting in Lisbon with Dr. Didier Prigent and Dr. Jacques Bartholeyns, April 2002, the
contents of the report as well as other work, weak points and strong points, were presented.
Furthermore a freedom to operate analysis of the technology used was presented to IDM.



Following completion of the contract Biotecnol continued to develop the process using a fusion
system in order to improve the yield, however success was limited and fusion systems were
considered non viable for development of an effective process. Biotecnol carried out work to
develop expression systems of greater potential which expressed non fusion IL13. This was
successfully achieved resulting in alternative options from which to develop, what is likely to
be, a more effective process.



In conclusion work performed by Biotecnol up until July 2002, developed a production prototype
using a system with a fusion partner, the process as presented would need further development
and optimisation to ensure it’s effective implementation and commercialisation for production
of a clinical grade IL13 meeting specifications and regulatory requirements relevant to it’s
end use.



Development and validation of suitable specifications and analytical protocols for process
control and batch release testing would require consideration along with formulation and
stability testing to meet the demands of regulations governing the production and
commercialisation of recombinant therapeutic proteins.



In this report we present IDM with an outline of our plans to develop a process using a system
expressing non fusion IL13 and to ensure the effective transfer and implementation of that
process, according to cGMP, for production of clinical grade IL13.



The specification for such product to be defined in consultation with IDM, for use in ex-vivo
cell therapy applications.



 









 








			
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2. Objectives




Over the past year Biotecnol have completed several bi-partite discussions with IDM and
more recently tri-partite discussions with Sanofi Synthelabo. Biotecnol presented a number of
documents in discussion of the continued activities covering technicalities and regulatory
issues of developing and transferring a process for production of a recombinant therapeutic
protein to cGMP quality.



These discussions have also considered IDM’s requirements in terms of product specifications
and the methodologies required to demonstrate compliance with those specifications. Further
consideration has been given to the quantities that will be required for IDM’s clinical trials
and eventual commercialisation of the technology.



On the basis of these discussions it is Biotecnol’s understanding that objectives of this
project are:-




	 	1.	 	Produce, characterise a sample of IL13 using Biotecnol’s pR expression
system, for comparison with the IL13 previously used by IDM.
	 
	 	2.	 	Outsource the production and testing, according to regulatory
requirements, of Master and Working Cell Banks of the chosen expression system.
	 
	 	3.	 	Develop a manufacturing process that can be effectively validated and
used for commercial manufacture of IL13 of a specification, equivalent to Sanofi
Synthelabo’s reference standard and specifications defined by further analysis
beyond that carried out by Sanofi Synthelabo (SaSy), in full compliance with cGMP
for production of recombinant protein Product Finished Product for implementation at
minimally 50 litre fermenter yielding up a minimum of 35 mg/I.
	 
	 	4.	 	Biotecnol will co-ordinate the effective transfer and implementation of
the manufacturing process at a cGMP facility chosen in consultation with IDM to
produce an initial batch of Finished Product to be used as a raw material for ex
vivo processing of human cell therapy products that are intended for phase III
clinical trials and commercial distribution.
	 
	 	5.	 	Biotecnol will have responsibility to develop the analytical protocols,
either in house, or in collaboration with a suitable CAL (Contract Analytical Lab),
said CAL agreed upon with IDM.
	 
	 	6.	 	Biotecnol will have responsibility to oversee the CAL to validate the
analytical protocols in compliance with GLP/cGMP.
	 
	 	7.	 	Biotecnol will have responsibility to oversee the CAL for lot release
testing.
	 
	 	8.	 	Biotecnol will have responsibility to oversee the contract manufacturer
to validate the process, equipment, or facility in compliance with GLP/cGMP.






 









 









	 	9.	 	Biotecnol will have responsibility to oversee the contract manufacturer
to release the drug product to IDM requirements
	 
	 	10.	 	Biotecnol will manage and oversee all aforementioned activities to ensure
the production and control of IL13, at the chosen contract manufacturer or CAL ,
suitable for use in phase III clinical trials and commercial distribution of IDM’s
cell therapy in the US and Europe. This will cover Prevention of cross contamination
during manufacturing, raw material control and management and minimum validation of
all processes, equipment, facility and personal that affect the safety of IL13 (e.g.
cleaning, aseptic steps, etc;) for clinical trial and commercialisation.





Further consideration must also be given to (Part II):




	 	1.	 	Formulation, containment and filling to produce the Finished Product.
	 
	 	2.	 	Stress testing to identify stability indicating assays to be used in stability
testing.
	 
	 	3.	 	Stability testing of the Product and Finished Product.
	 
	 	4.	 	Process Validation for commercialisation.




3. The Approach




A process to be compliant with regulatory authorities is not a trivial task to achieve.
It requires a multidisciplinary approach drawing knowledge from several fields.



A pro-active, flexible and evolving product development plan that integrates the activities
of all relevant functions from process / analytical development, manufacturing, quality
control, quality assurance and regulatory can help minimize unnecessary costs both in
resources and time.



Biotecnol’s emphasizes, early in the development of the process, the necessity for effective
interaction with the chosen cGMP facility and CAL to ensure development of viable protocols
for manufacturing and quality control. This interaction can only be achieved by effective and
regular communication by telephone and meetings between responsible personnel. This can only
be achieved by early and up front commitment of work to the chosen cGMP and CAL



Development work at Biotecnol will generate the necessary, methodologies and SOP’s, in
consultation with the cGMP facility and CAL, to ensure that the process and analytical
methodologies can be rapidly transferred and effectively implemented.



Work will be documented and reports compiled in line with an agreed work plan and the
requirements for provision of information and data for preparation of the CMC, and other
regulatory documentation.



 









 





			
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All draft specifications for release of the Finished Product for use in phase III clinical
trials or commercial distribution must be developed prior to the production and agreed by
IDM.



All draft specifications for stability testing of the Product and Finished Product for use in
phase III clinical trials or commercial distribution must be developed prior to the
production and agreed by IDM. Such specifications can only be developed if sufficient
preliminary stability information is available to draft the specifications i.e. this requires
a early commitment to the preliminary stability work herein proposed in order to have the
information available in good time to draft such specification prior to production.



The tasks to be undertaken, the periods over which those tasks will be implemented, and the
expected outputs in pursuance of the aforementioned objectives, are described in the revised
work program presented in section 4. This program has been revised from a prior outline of
the work program presented 09-05-03.


4. Work Program




PART ONE




T1 Identification of manufacturing facility.




Milestone — September 2003 -



Identification of potential candidates through telephone calls, internet search and meetings at
conferences



Preliminary telephone discussions with prospective candidates.



Visits to short-listed candidates for technical discussions and quality audits.



Deliverables T1P1



Initial Screening Reports — Biotecnol Visits

reports — Biotecnol

Audit reports — IDM

Comparison — Report Biotecnol Recommendation

Confirmation of manufacturing facility to move forward




T2 Production of IL13 from Biotecnol’s pR expression system.




Milestone 30th September 2003



Processing of pR sample for evaluation using existing protocol and comparison with SaSy’s IL13.



 









 





IL13 from Biotecnol’s clone will be produced and processed using the existing protocol and
compared with material produced by the SaSy’s clone.



Comparison with acceptance criteria will be made on the basis of:-




	 	i.	 	Reverse Phase HPLC — Typical profile to that obtained with Sasy’s IL13.
	 
	 	ii.	 	SDS PAGE — Reducing and Non reducing — Typical profile compared with
that of Sasy’s IL13.
	 
	 	iii.	 	N terminal sequencing — identical N terminal sequence to that of
Sasy’s IL13.
	 
	 	iv.	 	Amino Acid Composition — As expected for Sasy’s IL13
	 
	 	v.	 	Mass determination — Expected Molecular Mass
	 
	 	vi.	 	Bioactivity — Activity in the range of the activity of Sasy’s IL13





Functional evaluation, by IDM, of IL13 produced. IDM to input acceptance criteria.



Genetic Stability of the construct in the laboratory fermentation process



Fermentations will be analysed for plasmid stability based on the following methods and
acceptance criteria




	 	i.	 	Selective plating — plasmid retention > 80%
	 
	 	ii.	 	Restriction mapping — expected banding patter form restriction digest of
plasmid with several enzymes
	 
	 	iii.	 	Sequence of insert — sequence equivalent at end of fermentation to that
page 7 of 31 of the sequence of the vector
	 
	 	iv.	 	Expression levels — expression levels reproducible by SDS PAGE analysis.





Deliverables — T2P2



Reports on activities undertaken including methods used and results obtained



Successful processing and characterisation of functional IL13 at 10 mg/l.



Genetic stability of the vector construct during fermentation




 










 







			
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T3 Cell Banking




Dependent on successful completion of T2




T3P1 Milestone — Initiation of cell banking October 2004



T3P2 Biotecnol will supply to CeIITec a well characterised, purified plasmid. This
will be used to transform qualified BL12 strain. From the plating 10 colonies will be cultured
and stored as 10 glycerol stocks. These stocks will be analysed for expression level, SDS
PAGE, against Biotecnol’s development cell bank. The best production stock will be recommended
and further qualified in fermentation experiments at Biotecnol




T3P2 Milestone — Production of MCB and WCB 23rd January 2004



From this stock MCB and WCB (220 vials each) will be established. Production will be carried
out in Category A laminar flow cabinet in a category B room. All media and buffers used for
production of cell banks are free of animal derived compounds.




T3P3 Milestone — Testing and Release of MCB/WCB 21st May 2004



10 vial of each cell bank will be used for the testing and analysed in accordance with ICH
guidelines as defined in the contract.




	 	 	 	 	 
	Phenotype Characterisation

	 	API20E
	 	Conforms with CSS
	Genotype

	 	RAPD
	 	Conforms with CSS
	Viability

	 	Plating assay
	 	> 1X107 CFUs/ml
	Copy Number

	 	Photometric
	 	 
	Sequence Identity

	 	Restriction Map
	 	Expected pattern
	 

	 	Sequencing insert
	 	Conforms to ref. sequence






	 	 	 	 	 	 	 
	 

	 	Contamination
	 	Selective Plating
	 	Absence of contaminants
	 

	 	 
	 	Microscopy
	 	 
	 

	 	 
	 	Gram Staining
	 	 
	 

	 	 
	 	Phage Plaque Assay
	 	Absence of Phage
	 

	 	Plasmid Stability
	 	Replica Plating
	 	 
	 

	 	Growth Characteristics
	 	OD
	 	Conforms with CSS
	 

	 	 	 	Biomass
	 	Conforms with CSS
	 

	 	 	 	SDS PAGE
	 	Conforms with CSS






Deliverables — T3




Development Report for establishment of the CSS Executed Batch Records

for MCB and WCB SOPs for preparation of buffers and media

CofA for all raw materials

Testing records

CofA for final release of MCB and WCB




 









 





T4 Process Development — Fermentation




T4P1 Milestone —Initiation of development activities — fermentation April 1st 2003




T4P2 Milestone - Continued development — fermentation September 30th 2003




T4P3 Milestone — Fermentation Protocol — September 2003



Activities to define the fermentation process.




	 	 	 
	1.

	 	Shake Flask Evaluations.
	2.

	 	Initial evaluation in the fermenter.
	3.

	 	Optimisation and verification of a batch process.
	4.

	 	Optimisation and verification of fed batch process.
	5.

	 	Comparison of productivity.





From this the following parameters will be defined.





	 	§	 	Medium components — Inoculum and fermentation




(no materials for which non-animal derived sources exist will be used in the media.)





	 	§	 	Inoculum Regime.
	 	§	 	Feeding strategy.
	 	§	 	Dissolved Oxygen — DO.
	 	§	 	pH.
	 	§	 	Temperature.
	 	§	 	Point of induction.
	 	§	 	Harvest time — post induction.




Outputs from this study will include





	 	§	 	Growth Characteristics — OD and Cell Dry Weight.
	 
	 	§	 	SDS PAGE analysis of expression levels.
	 
	 	§	 	On line data for DO, Agitation, pH and temperature.





Deliverables T4P3



Detailed report describing work carried out and conditions defining the process for further
characterisation.




 









 








			
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T4P4 Milestone — Consistent Laboratory Fermentation Process — December 2003.



Characterisation will be carried out in a test range to avoid inevitable failure but wide enough to
see failure if the parameter is critical.



The process inputs are:




	 	 	 	 	 
	•

	 	Inoculum Regime
	 	+/- 15%
	•

	 	Feeding strategy
	 	+/- 15%
	•

	 	Dissolved Oxygen — DO
	 	+/- 10%
	•

	 	PH
	 	+/- 0.5
	•

	 	Growth Temperature
	 	+/- 3°C
	•

	 	Induction temperature
	 	+/- 3°C
	•

	 	Point of induction
	 	+/-10%
	•

	 	Harvest time
	 	+/- 15%





Process outputs will include




	 	 	 	 	 	 	 
	•	 	On line data DO, pH, temperature
	•	 	Growth Profiles OD , CDW
	•

	 	Acetate Levels	 	 	 	 
	•

	 	Expression Levels
	 	SDS PAGE	 	 
	 

	 	 	 	HPLC	 	 
	•

	 	Plasmid Stability
	 	selective plating	 	 





Those parameters where it is observed that a greater than 15% difference exists in one of the
output variables will be investigated further over a narrower range to identify edge of
failure limits.



On completion of the above the process a minimum of three batches will be performed at a 5
litre working volume to demonstrate that the process is controlled within the ranges as
specified by the above studies.



Process outputs will include




	 	 	 	 	 	 	 
	•	 	On line data DO, pH, temperature, CO2, 02
	•	 	Growth Profiles OD , CDW	 	 
	•	 	Acetate Levels	 	 
	•

	 	Expression Levels
	 	SDS PAGE	 	 
	 

	 	 	 	HPLC	 	 
	•

	 	Plasmid Stability
	 	restriction maps	 	 
	 

	 	 	 	selective plating	 	 
	 

	 	 	 	sequence analysis of the IL13 insert.	 	 





In parallel to this work the stability of the plasmid will be further studied, beyond the
generations expected in the production process. This will be carried
out by growing the cells using the conditions identified in the initial definition. Serial subculture will be
carried out to imitate the number of generations expected when the fermentation process is
scaled to 200 litres.



The process outputs will include




 









 








	 	 	 	 	 	 	 
	•	 	On line data DO, pH, temperature
	•	 	Growth Profiles OD , CDW
	•

	 	Acetate Levels	 	 	 	 
	•

	 	Expression Levels
	 	SDS PAGE	 	 
	 

	 	 	 	HPLC	 	 
	•

	 	Plasmid Stability
	 	restriction maps	 	 
	 

	 	 	 	selective plating	 	 






Deliverables T4P4



A report will be compiled of the work carried out and the results obtained.



A full process description will be produced defining the medium components, their source and
preparation, operating parameters, limit values. Methods used in analysis of outputs and the
data obtained from the consistency batches. This will serve as the technology transfer working
document for the fermentation process.




T5 Process Development: DSP




	 	 	 
	T5P1

	 	Milestone — Initiation of development work — DSP. April 1st 2003
	 
	 	 
	T5 P2

	 	Milestone — Continuation of development work — DSP . September 30th 2003
	 
	 	 
	T5 P3

	 	Milestone — DSP protocol — December 2003





A strategy to extract, refold and purify the IL13 produced by E.coli will be developed.




Step 1



Cells from fermentation experiments will be harvested in a centrifuge with a capacity of 1.5
litres.



Subsequent to harvest the cells will be resuspended in an appropriate buffer, typically Tris,
EDTA and disrupted using a high-pressure homogeniser. Initially protein release into the
soluble phase, as determined by colorimetric analysis, will be used to follow the
effectiveness of the disruption process.




 









 








			
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	 	13-Nov-03






Step 2



The following parameters will be defined





	 	•	 	Equipment model, manufacturers
	 	•	 	Buffer pH and composition
	 	•	 	Concentrations at resuspension — OD and or wet weights
	 	•	 	Pressures
	 	•	 	Temperatures
	 	•	 	Centrifugal forces
	 	•	 	Cycles / Passes
	 	•	 	Temperatures
	 	•	 	Storage conditions
	 	•	 	Times




Following disruption the inclusion bodies will be recovered by centrifugation and washed
several times. The washing process will be studied to determine a strategy to wash away any
contaminating proteins early in the process so ensuring that the starting material is as pure
as possible. It is likely that a combination of chaotropic agents in low concentration and
aqueous washes will be sufficient to effectively wash the inclusion bodies. We will not want
to use more than three washing steps, preferably 2 steps or less will be our ultimate aim. The
effectiveness of the washing step will be visualized by SDS PAGE analysis of the inclusion
bodies solubilised in SDS. The weights of pellets recovered after each stage will be
determined.



Process outputs will include:





	 	§	 	Protein quantification and SDS PAGE analysis




It is unlikely that the chosen facility will have the same system for centrifugation and
disruption as used at Biotecnol. The information and results presented in this report will
serve as a benchmark to effectively re-optimize at the manufacturing facility in consideration
of the equipment available and ensue that the process is effectively scaled to produce
inclusion bodies of the same standard.




Step 3



Following extraction and washing of inclusion bodies the inclusion bodies will be solubilised
in Guanidine. Effectiveness of solubilisation will be monitored by HPLC and solids remaining
using wet weight determinations following centrifugation.



The following key parameters will be defined.





	 	•	 	Equipment model and manufacturer
	 	•	 	Temperature
	 	•	 	Composition and pH of solubilising agent
	 	•	 	Concentration for resuspension — wet weight
	 	•	 	Time
	 	•	 	Agitation
	 	•	 	Viscocity of solubilised inclusion bodies




 









 










Process outputs will include





	 	•	 	HPLC analysis
	 	•	 	Solids Remaining





Step 4



Prior to refolding solubilised inclusion bodies will be clarified in order to remove non-soluble
material. Effectiveness of this step will be determined using dry weight measurements post and
pre filtration and analysis by reverse phase HPLC.



The key parameters will be defined.





	 	•	 	Equipment Model and manufacturer
	 	•	 	Membrane Specifications
	 	•	 	Volumes
	 	•	 	Flow rates
	 	•	 	Pressures
	 	•	 	Time
	 	•	 	Temperature




Process outputs will include





	 	•	 	Reverse phase analysis
	 	•	 	Dry weight determinations





Step 5



The clarified inclusion bodies will be subsequently refolded. The conditions for refolding
will be studied so as to identify the conditions giving the desired yield > 35 mg/l and
purity (see following step) on further processing. Reverse phase analysis will be used to follow
the refolding process in order to reject those less promising conditions. Those conditions,
which, on HPLC analysis show more promise, i.e. a significant proportion of IL13 in its oxidized
and native state, as compared with the reference standard, will be subject to further processing
to identify the subsequent recovery. Those options giving the highest yield will be considered
for further optimization in consideration of minimizing the volumes in which refolding is
carried out.



The following parameters will be defined:





	 	•	 	Composition and pH of refolding buffer
	 	•	 	Concentration/dilution factor for refolding
	 	•	 	Dilution Rate
	 	•	 	pH adjustments
	 	•	 	Time
	 	•	 	Temperature
	 	•	 	Agitation




Outputs will include





	 	•	 	Reverse phase analysis — quantification of refolding process






 










 









			
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Step 6



On completion of refolding the solution may require further clarifications and concentration
before progressing to the next stage of the process.



Following parameters will be defined




	 	•	 	Equipment Model and manufacturer
	 	•	 	Membrane Specifications
	 	•	 	Volumes
	 	•	 	Flow rates
	 	•	 	Pressures
	 	•	 	Time
	 	•	 	Temperature





Reverse phase HPLC analysis will be used to monitor this step and define any losses or
modifications occurring.



Output




	 	•	 	Reverse phase analysis and quantification of losses





Step 7



In the next phase of the program the primary goal will be to capture IL13 directly from the
preceding step, as this will likely provide the most efficient means of processing IL13 further.
HIC or CatX chromatography are the most likely options to succeed in this step. Several media
types will be studied for their ability to capture pure IL13 and its effective elution.
Conditioning may also be required and these will have to be determined. Those media shown to
effectively capture pure IL13 will be tested for their ability to capture IL13 subsequent to
refolding. The success of this capture step will be determined by reverse phase HPLC, SDS PAGE
and Bioactivity to demonstrate that the product is typical and that the yields are sufficient to
result in a final yield of at least 30 mg/l.



The following parameters will be defined




	 	•	 	Feed conditioning requirements
	 	•	 	Protein concentration of feed
	 	•	 	Feed pH, conductivity and pH
	 	•	 	Equipment model and manufacturer
	 	•	 	Chromatography media specifications
	 	•	 	Column Specifications
	 	•	 	Packing Protocol and specifications
	 	•	 	Temperatures
	 	•	 	Pressures
	 	•	 	Buffer compositions, pH and conductivity.
	 	•	 	Equilibration flow rates and volumes
	 	•	 	Feed flow rates, volumes/capacity
	 	•	 	Wash volumes and flow rates
	 	•	 	Elution conditions, volumes, flow rate, gradients.
	 	•	 	Regeneration, flow rates and volumes.
	 	•	 	Eluate volume, concentration, pH and conductivity.





Outputs will include



 









 







	 	•	 	SOP for column packing and testing
	 	•	 	Chromatograms
	 	•	 	HPLC analysis — quantification and identification
	 	•	 	SDS PAGE analysis
	 	•	 	Bioactivity





At the point that it is considered that the capture step is effective and provides a sample of
IL13 giving typical bioactivity, HPLC profile and SDS PAGE, further analysis will be performed
to ascertain the extent of DNA, Host Cell Protein and Endotoxin removal in establishing whether
a further step might be required to reduce these contaminants to acceptable levels (note: these
level have yet to be defined for this type of product, IDM input). In the extent that these
contaminants are above specification then it will be desirable to introduce an anion exchange
step or membrane step to capture such contaminants. If needed the conditions will be defined
and results presented. (See previous chromatography and membrane steps for typical conditions
to be defined and outputs)



Outputs also include




	 	•	 	DNA determination
	 	•	 	Host Cell Protein Determination
	 	•	 	Endotoxin determination





Step 8




Analytical SEC will also be performed to ascertain the extent to which aggregates are present
and may need removing. Their removal can generally be accomplished using preparative SEC. It is
most likely that Sepahcryl 100 or Sephadex 75 will be suitable for this application. In order
to maximize the productivity it is likely that prior to introduction of such a step further
concentration will be required. This might be achieved by the application of a further capture
of the purified product via cation exchange chromatography or concentration using tangential
flow filtration. If needed the conditions will be defined and results presented. (See previous
chromatography and membrane steps for typical conditions to be defined and outputs).



T5P3 Deliverables




A report will be compiled covering the results of activities and defining the process for
extraction and purification (DSP) for further characterization



 









 





			
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T5P4 Milestone — Consistent DSP protocol — April 2004




The process will be characterized further. It is expected when this activity begins the CMO will
have been selected and a commitment made in initiating technology transfer. It will be expected
that communication takes place between Biotecnol and the CMO to establish process fit for the DSP
and critical issues in consideration of the scale-up for effective functioning of DSP on the
operating units available at the cGMP. The main issues, the selection of membranes equivalent to
those used at the cGMP facility and issues relating to solubilisation and refolding. Chromatography
steps should scale linearly for the scale expected in manufacturing. With input from the CMO
further modifications to the lab scale process, which could assist in transferring the technology,
will be implemented and tested.



The steps might be further optimized to improve productivity. The requirement for this will depend
on the outcome of T5P3 and the projected requirements for processing of larger volumes in the cGMP
facility. Typically productivity can be improved as a consequence of alterations to fluxes, feed
volumes/maximizing capacity, volumes for equilibration, washing and elution and typically these
will be the parameters targeted for further optimization if deemed necessary.



Process characterization will take the form of “range-finding”.



Process inputs will include




	 	 	 	 	 
	•

	 	Resuspension concentrations
	 	+/- 20 %
	•

	 	Feed pH
	 	+/- 0.5
	•

	 	Temperature
	 	+/- 3°C
	•

	 	Load capacity
	 	+/- 15%
	•

	 	Dilution rate / volume
	 	+/- 15 %
	•

	 	Elution profiles
	 	+/-15%
	•

	 	Conductivity
	 	+/- 10%






Process outputs will include





	•	 	On line data — chromatograms, UV absorbance, pH , conductivity, pressure, flow rates
	 
	•	 	In process analytical data — SDS PAGE, Reverse Phase HPLC, DNA and HCPs
	 
	•	 	Final Product — SDS PAGE, Reverse Phase HPLC, SEC HPLC, Bioactivity, HCPs, DNA and
endotoxins, n-terminal sequencing.





Those parameters where it is observed that the analytical data is atypical of the data obtained
from development of the process will be investigated over a narrower range to identify edge of
failure limits.



Hold times and temperatures will be studied in 1 batch up to 24 hours between each step.



On completion of the above process the reproducibility will be established by repeating the process
three times processing a minimum of 1 liter from 3 X 5 liter fermentation batches.



 









 





Deliverables T5P4




A report will be prepared describing the work and conditions used in testing reproducibility of the
DSP strategy.



A full process description will be produced defining the buffer components, their source and
preparation operating parameters, limit values. Methods used in analysis of outputs and the data
obtained from the consistency batches. This will serve as the technology transfer working document
for the DSP process.


T6 Development of analytical methods for process monitoring, and lot release testing.




T6P1 Milestone — Initiation of analytical development — April 1st 2003



T6P2 Milestone — Analytical SOPs — December 2003



ICH Topic Q6B Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Product gives guidance on the general principles and considerations for
the setting and justification of specifications for biotechnological products. The product itself
must be characterised in relation to it’s physicochemical properties, biological activity, purity,
impurity, contaminants and quantity. Adequate in process controls must be developed and adopted to
demonstrate and monitor consistent perform of the process as part of the overall assurance of
quality of the final product. Specification must be set and justified taking into account
analytical procedures based on lots used in preclinical, clinical studies, demonstration of
manufacturing consistency and stability for both Product and Finished Product.



During the period in which the process is being developed several assays will be used, adapted and
developed further for process monitoring and lot release testing.



Reverse Phase HPLC — quantification, identity and purity. In general it is useful to distinguish
between misfolded, reduced and partially oxidised forms. Calibration curves will be established
using the Sasy’s reference material. Biotecnol’s development process will be monitored and
quantified against this reference material.



SEC HPLC — quantification, purity and estimation of Mw. It is useful to distinguish aggregates from
monomers and larger molecular weight contaminating molecules. Sasy’s reference material will be
used to generate calibration data. Low Molecular Weight Markers will be used to calibrate the
column for estimation of the molecular weights of the IL13 and contaminating species.



SDS PAGE — indicate purity of product and relative levels of expression. Homogeneous gels, both




reducing and non-reducing will be carried out. Pharmacopoeial like analysis, using the Sasy’s
material as



 









 





			
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a reference will be developed as a means to assessing the relative purity.



Ion Exchange HPLC — Isoforms with different charges e.g. deamidated, have potential to be resolved
using analytical ion X chromatography.



Host cell DNA. It is not expected that a specific host cell DNA assay will be routinely required,
however an in-house colorimetric hybridisation assay will be developed, using purified DNA (genomic
and plasmid) from the host strain.



Host Cell Proteins It is not expected that a specific host cell protein assay will be required. A
generic test based on ELISA or Immunoblots and currently available on the market (Cygnus) will be
evaluated, using the supplied reference standards to determine the levels of HCPs present in the
product.



Peptide mapping. The development of this methodology if required will be outsourced to M-Scan. .



Sequence and amino acid analysis, where required, will be outsourced during development work to
M-Scan or Eurosequence .



Endotoxins. Endotoxins will be determined in house using LAL kit from Biowhitaker/Charles Rivers.



In vitro biological activity — determined by proliferation assay using TF1 cells. This method has
been established at Biotecnol and will be routinely used in the determination of bioactivity.



Process Related Impurities.




Since the process is not yet defined we cannot yet develop assays for process related impurities.
On completion of T5P3 we will have a clearer idea of the process related contaminants for which we
may have to test and can develop the assays accordingly. The current components that are most
likely to require assays are



                    Guanidine,

                    Glutathione

                    DTT

                    Kanamycin




 









 





Deliverables T6P2




For all the above methodologies SOPs will be written detailing




	 	•	 	Instruments used.
	 
	 	•	 	Column specifications and suppliers
	 
	 	•	 	Reagents and suppliers
	 
	 	•	 	Kits and their suppliers
	 
	 	•	 	Procedures.





T6P3 Milestone — Methods Transferred to CMO — 19th March 2004




T6P4 Milestone — Validated Analytical Protocols — 30th July 2004




ICH Q2 A (Text on validation of analytical procedures), Q2B Validation of analytical procedures,
methodology) and FDA — Analytical Procedures and Methods Validation provide guidelines to the
validation requirements for analytical procedures relating to analytical methods for assuring
identity, purity quantities and activity of a Product /Finished product.



Typical validation characteristics that will be considered.



System Suitability — generally replicate loadings of (n=3) of a suitable reference standard and
where available a second component e.g. nominated decomposition product. Retention time and
migration variance of less than 3% and area and band volume variances of less than 10%.



Specificity — Ability to assess unequivocally the analyte in the presence of other component which
might be expected to be present. Comparison of degraded samples and samples with known impurities
with a reference sample



Linearity — the ability of the method to obtain results which are directly proportional to
concentration of the analyte. Generally obtained by dilution of increasing volumes of a stock
solution of reference standard and or analyte in presence of formulation agents with known
concentration (e.g. 6 dilutions in duplicate) this will give a working range and define limits of
detection and quantification for the analyte . R2 Value should be equal to or greater than 0.95.



Accuracy — Checks using formulation buffer spiked with known concentrations of analyte quantitated
using the linearity plot. Recovery should fall within 80-115% of expected.



Repeatability
— Carrying out analysis in six replicates over a short period of time on one instrument. %CV (Coefficient of Variation) less than or equal to 10%.



Intermediate precision — method run on different days or by different operator. 6 aliquots analysed
in



 









 





			
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duplicate on different days. %CV less than or equal to 10%.



Robustness — Generally experiments should be designed to consider the following criteria




	 	 	 
	I.

	 	Stability of analytical procedures
	 
	 	 
	II.

	 	Variations of reagents
	 
	 	 
	III.

	 	Timing of steps
	 
	 	 
	IV.

	 	Temperature
	 
	 	 
	V.

	 	PH
	 
	 	 
	VI.

	 	Variation of, columns, gels, etc,.






The objective of the procedure should be clearly understood since this will govern the validation
characteristics which need to be evaluated. Testing for impurities can be either quantitative or
limit tests with different validation criteria.



At minimum the methods to be validated for lot release testing of IL13 to which the above criteria
will apply include



     • .. SDS PAGE — Identity, purity and apparent molecular weight

     • .. Immuno Blotting — Identity and possible host cell proteins

     • .. HCP, Threshold Method /ELISA — Purity

     • .. DNA, Threshold Method — Purity

     • .. Reverse Phase HPLC — Identity, purity and quantification

     •    SEC HPLC — Purity and identity




The current proliferation assay will be validated in consideration of the general requirements
to show:



System Suitability — e.g. use of a neutralising antibody




Specificity — The influence of buffer components and contaminants on the assay.



Linearity — The current assay defines the range over which the response is linear in order to
calculate activity.



Accuracy — Spiking with known amounts of analyte




Repeatability
— Due to the nature of the bioassay the precision is generally defined by replicates
of the same sample in the same assay to give the fiducial limits.



Intermediate Precision — Analysis of the same sample on a different day by a different operator.



Robustness. Generally experiments should be designed to consider the following criteria




	 	 	 
	I.

	 	Variations of reagents
	II.

	 	Timing of steps
	III.

	 	Temperature






 









 






	 	 	 
	IV.

	 	pH
	V.

	 	Variation of equipment






The following methods may also be required, whether they need to be validated for routine product
release needs to be discussed



Ion X or IEF

Peptide map — Identity



Extinction Coefficient — Amino Acid analysis — Quantification



MS — Molecular Weight



Deliverables T6P4




Reports




Instrument specifications, Materials and Methods



Analytical results, Chromatograms, Gels, Bioactivity Specifications of test methods


T7 Process Transfer to cGMP facility.




T7P1 Milestone — Initiation of transfer — January 2004




Following review and approval by IDM of a protocol for the transfer. IDM needs to define clearly
the information required in such a protocol for the transfer otherwise this is not a clear
milestone



T7P2 Milestone — Lab Scale process consistency at CMO — May 13th 2004





Supply of reference material — Biotecnol to CMO

Process Descriptions and data from — Biotecnol to CMO

Required analytical SOPs for process monitoring and product release. — Biotecnol to CMO

Review of documentation by CMO

Questions raised during review to be discussed

Definition of methods to be used in demonstrating equivalence.

Training of CMO Personnel — Process demonstration at Biotecnol

Implementation of laboratory process in 10 litre fermenter at CMO, said fermenter having
the downscaled specifications equivalent to that of the 200 litre fermenter. — Assisted
by Biotecnol personnel




Running of three laboratory batches processing a minimum of 5 litres thus providing an
effective scale factor for DSP in the final process, minimally 1:10 Testing of Product
produced by CMO at CMO, Biotecnol and CAL if needed.



 









 





			
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          Deliverables T7P2




A report describing three runs at laboratory scale demonstrating process performance equivalent to
that obtained at Biotecnol.



Identification of the key issues which will need to be addressed further in consideration of scale
up and implementation — report to be prepared by CMO and discussed with Biotecnol



Material from the three runs for further testing at Biotecnol.




Material from these runs can be further used as reference material by the CMO. Identification of
materials to be procured and qualified.



Product and process specification, test methods, online analysis and expected outcome required at
each stage of the process and for product release.



Testing results of Product by CMO, Biotecnol and CAL if needed.



T7P3 Milestone — Non-cGMP Process Demonstration at Scale — September 9th 2004



Step 1




Further optimisation in consideration of elements identified in T7P2 above to ensure process
fit. Most likely to be centrifugation, filtration and refolding steps but does not preclude work on
other steps where identified



Deliverables T7P3 — Step 1




Report on work carried out and demonstration of effectiveness of the optimised operation in
attaining the results demonstrated and specified in T7P2.



Description of the process to be carried out at scale.



Step 2




Consistency and Robustness will be demonstrated using scale down studies or, when necessary,
equipment at scale. The study will identify and demonstrate the control of the critical parameters.
The resulting ability of each step to achieve, reproducibly, its intended purpose, as defined by
the process data and analytical results.



During this stage the cleaning protocols will be defined.



Test specifications for materials requiring further qualification will be set and materials
qualified appropriately.



 









 





Deliverable T7P3 Step 2




Report detailing the Process, equipments, raw materials, procedures, on line data and off line
analysis demonstrating consistency and robustness of the process.



Cleaning and aseptic validation plan.



Equipment and facility validation plan



Qualification of raw materials



Step 3




Non cGMP Process Demonstration at Scale




The process will be run at scale, 200 litres fermentation, DSP using a minimum of 50 litres biomass
from the fermenter under non-cGMP conditions.



Deliverables T7P3 Step 3




Process functioning at scale in cGMP meeting specifications defined in T7P2 Batch of IL13,
non-cGMP



Batch production record and analytical SOPs for review.




CofA




T7P4 Milestone — cGMP Documentation Reviewed — September 16th 2004




Deliverables T7P4




All SOPs and Master batch production records will be finalised by CMO and reviewed by
Biotecnol and IDM.


T9 cGMP Batch Production and Analysis.




T9P1
Milestone — Initiation of Production — September 17th 2004




T9P2
Milestone — Release of cGMP Product — December 15 2004



 









 





			
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Deliverables T9P2




One batch run, cGMP compliant, at the manufacturing facility producing clinical/commercial
grade IL13 of the required specification for subsequent clinical use and commercial use Per IDM
requirements.



Documentation




SOPs — Manufacturing, Cleaning and Analytics




Batch Manufacturing Record and test results




CofA



PART II



T8 — Validation Master Plan




T8P1 —  Milestone — Initiation of Validation Master Plan — June 15th 2004




In order to ensure that the process can be validated for later commercialisation the necessary work
will be carried out in fully characterising the performance of the critical parameters, identified
during initial phases of T7P3 and the means by which those parameters will be monitored to generate
the required plan of activities in validating the process, the Validation Master Plan.



T8P2 —  Milestone — Delivery of Validation Master Plan — September 16th 2004




Deliverables T8P2




The Validation Master Plan will be finalised by CMO and reviewed by Biotecnol and IDM.



T10 Filling and finishing of Product to deliver Finished Product .




T1OP1 Milestone — Selection of manufacturer — March 2004



 









 





T10P2 Milestone — Initiation of manufacture — November 2004




T10P2
Milestone — Release of Finished Product — January 2005




IDM have provided an indication of the form in which they would like to provide the product. The
specifications given are:




	 	•	 	100 ug /ml (to be confirmed )
	 
	 	•	 	2 ml type I glass vials
	 
	 	•	 	Halobutyl stoppered
	 
	 	•	 	fill volume between 0.5 ml to 3 ml
	 
	 	•	 	Storage at -70°C.( to be confirmed with preliminary stability results)





IDM have yet to provide details on the number of doses they require from the fist batch




Aseptic filling will be outsourced. The availability of suitable facilities will depend on the
number of vials required and the availability of freezing units. From feedback, so far obtained
from several facilities, the availability of freezer units at — 70°C could present the biggest
hurdle, some facilities would procure, passing on the cost of procurement and validation to the
customer.



There is some recent suggestion that IDM may now have different requirement with regards to the
container type and filling operation, this needs to be clarified to proceed with implementation
of this task



Deliverables T1OP3



One batch of finished Finished Product (No of vials to be specified by IDM)

SOPs

Batch Manufacturing Records

CofA




 









 





			
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T11
Generation of Preliminary Data to Demonstrate Product Stability.




T11P1 Milestone — Initiation — October 2003



Biotecnol presented a previous document to IDM “Considerations in Testing Stability of IL13”
based on their concerns that this issue was not being given enough attention. In that document
the regulatory considerations were outlined.



T11P2 Milestone — Preliminary Stability Data — January 2004



International Conference on Harmonisation : Final Guidance on Stability Testing of
Biotechnological / Biological Products — 7/10/1996 should be considered.



Preliminary investigations should be conducted. It is important to consider the presentation of
IL13 both as Product and the form in which it will be presented for end use i.e. finished
product. This work could begin with materials generated in the laboratories and would be
continued using material generated during process transfer. It would be the intention, during
this time, to generate methods and data to define the stability protocol for monitoring the
materials produced for clinical trials and ultimately the program to be conducted in support of
a regulatory submission.



Consideration should be given, at minimum, to storage temperatures, analysis of potency
(Bioassay), degradation products (reverse phase HPLC, SDS PAGE and SEC HPLC are typically used).



Biotecnol would propose preliminary studies on material to be produced using the current process
to ascertain the ability of assays to detect degradation products and obtain some initial idea
on IL13 stability.



Three temperatures would be selected — 70°C, 4 — 8°C and 25°C. The samples would be stored in
cryo-vials at circa 100 ug /ml in 50 mM ammonium acetate pH 6. Storage units for these
conditions are available at Biotecnol and the units monitored. 2 materials would be stored at
each temperature and analysed in duplicate assays by SDS PAGE, Reverse Phase HPLC, SEC HPLC,
Bioactivity. Analysis would be carried out at T=O, 4, 8, 16, 32 and 64 days. Bioactivity would
be performed on -70°C sample at T 32 and 64 days only as we are already confident that the
activity is considerably stable at this temperature.



The results from this study would give us a preliminary indication of the stability of the
product at different temperatures and whether we might need to consider further the
stabilisation of the product. This is critical to know before we invest in the stability study
of cGMP batches of material and also to support



 









 







the CMC for phase III. At 25 °C we would expect to see some degradation and this would confirm
the effectiveness of the assays



Deliverables T11 P2



Instrument specifications, materials and methods



Analytical results, chromatograms, gels, bioactivity



Indication of the need for further formulation



Indication of assays ability to detect degradation.



T11P3 Milestone — Intermediate Stability Data — November 2004




When the process is more fully defined, T5P3, further material could be produced and stored at
relevant conditions, (- 70, - 20 and 2-8 °C) and studied in consideration of previous results eg
1, 2, 3, 6 and 9 months.



Deliverables T11 P3



Reports



Instrument specifications, materials and methods

Analytical results, chromatograms, gels, bioactivity

Indication of the need for further formulation

Indication of assays ability to detect degradation.




T11P4 Validation of Stability Indicating Assays.




It is proposed that Sterility, endotoxin, SDS PAGE, Reverse Phase HPLC, SEC HPLC, IonX HPLC and
Bioactivity will be used in the stability study on the Finished Product to demonstrate shelf
life.



These methods will have been validated for product release, however it needs to be discussed
further whether these methods, or other proposed for this study, require further validation as
stability indicating assays.



In general this may be as simple as demonstrating that the assays can detect degradation
products by deliberately exposing the product to stress conditions — high temperature, pH
extremes, oxidation, shear.



We should as minimum be able to define the detection limits of our assays.



This activity will have to have been completed before the studies on the cGMP lot begins.



 









 





			
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T12 Stability Studies on cGMP Grade Product and



Finished Product .




T12P1 Milestone — Initiation of Stability Studies — February 2005.




Stability Studies on Product and Finished Product will be carried out according to the program
discussed with IDM and Sanofi Synthelabo, at 25°C, 2-8°C
and - 70°C.



The program considers the following criteria



	 	 	 	 	 
	•

	 	Sterility
	 	single assay
	•

	 	Endotoxin
	 	single assay
	•

	 	Appearance
	 	single observation
	•

	 	PH
	 	single measurement
	•

	 	Bioactivity
	 	triplicate assay
	•

	 	SEC HPLC
	 	triplicate assay
	•

	 	SDS PAGE
	 	duplicate assay
	•

	 	Reverse Phase HPLC
	 	triplicate assay
	•

	 	IonX HPLC
	 	triplicate assay






Excel spreadsheets with updated analytical test results during the ongoing study will be sent
after each time point.



The choice of the Outsourcer will need to be discussed and decided before February 2004.



Deliverables T12



Interim reports on stability will be issued every 6 months.
Completed reports will be issued at the end of the study at



T12P2 25°C, February 30th 2005.



T12P3 2-8°C May 30th 2005



A completed stability report detailing the methods and results will be provided after 12, 24 and
36 months for the temperature at which the product is intended to be stored long term (-70°C)



 









 





T12P4     August 2005             6 months stability data — interim report.



T12P5     February 2006        1 year stability data — completed report.



T12P6     August 2006            1.5 years stability data — interim report



T12P6     February 2007         2 years stability data — complete report



T12P6     August 2007           2.5 years stability data — interim report



T12P6     February 2008       3 years stability data — complete report



 









 





			
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SCHEDULE 2








	200320042005
IDNameJ F M A M J J A S 0 NFA M J J ,à0
1TOP01-04
2Tl PIidentif CMG
TIP1150
3T2P2functional Bî_13
T2P50
4T3P130-09
5T3P2MOB WCB prod
T3P230
5T3P3 MOB WCB release T3P3 i 40
7T4P1 initiation fermentation
T4P150
8T4P2
30-09
9T4P3fermep tation protocol
T4P375
10T4P4reproducible lab ferment proc
T4P4 +100
11T5P101-04
12T5P2; 30-09
13T5P3DSP protocol
T5P3
14T5P475 reproduc ble lab DSP proc T5P4100
T6P1 01-04
T6P2analyticals SOPs T6P2
17T6P3
18T6P4
19T7P1
20T7P2
21T7P31
22T7P4
23T9P1
24T9P2